Vedolizumab (Entyvio)

Vedolizumab (Entyvio)
F. Wilson Jackson, MD

IBD Autoimmune inflammatory disease
Activated WBC central to disease progression Activated T-Cells

Geographic Distribution of IBD

Crohn’s Disease: Anatomic Distribution
Small bowel alone (33%) Ileocolic (45%) Colon alone (20%) Freq of involvement Most Least

Other area of involvement
Eyes Liver Joints Skin Kidneys

Normal anatomy Terminal ileum

Inflammation of the bowel

Colitis

Inductive Therapies for Crohn’s Disease
Aminosalicylates Antibiotics Corticosteroids Infliximab

Therapeutic Pyramid for Active Crohn’s Disease
Surgery Severe Immunomodulators Infliximab (Prednisone) ? Moderate Corticosteroids The therapeutic pyramid for Crohn’s disease is based upon clinical trials. Controlled release budesonide has been advocated for mild-moderate disease in countries where it is available. Infliximab has been efficacious independent of concomitant medications. (Budesonide) Mild Aminosalicylates/Antibiotics

Nielsen OH, Ainsworth MA. N Engl J Med 2013;369:754-762.
Algorithm for the Use of TNF Inhibitors in Patients with Inflammatory Bowel Disease. Figure 2. Algorithm for the Use of TNF Inhibitors in Patients with Inflammatory Bowel Disease. This algorithm depicts the conventional step-up strategy used in the treatment of ulcerative colitis and Crohn's disease. 5-ASA denotes 5-aminosalicylic acid. Nielsen OH, Ainsworth MA. N Engl J Med 2013;369:

Abraham C, Cho JH. N Engl J Med 2009;361:2066-2078.
The Intestinal Immune System. Figure 1. The Intestinal Immune System. In the healthy state, the goblet cells secrete a layer of mucus that limits exposure of the intestinal epithelial cells to bacteria. Both the secretion of antimicrobial peptides (e.g., α-defensins) by Paneth cells and the production of immunoglobulin A (IgA) provide additional protection from luminal microbiota. Innate microbial sensing by epithelial cells, dendritic cells, and macrophages is mediated through pattern-recognition receptors such as toll-like receptors and nucleotide oligomerization domain (NOD) proteins. Dendritic cells present antigens to naive CD4+ T cells in secondary lymphoid organs (Peyer's patches and mesenteric lymph nodes), where factors such as the phenotype of the antigen-presenting cells and the cytokine milieu (transforming growth factor β [TGF-β] and interleukin-10) modulate differentiation of CD4+ T-cell subgroups with characteristic cytokine profiles (regulatory T cells [e.g., Treg] and helper T cells [e.g., Th1, Th2, and Th17]), and enterotropic molecules (e.g., α4β7) are induced that provide for gut homing of lymphocytes from the systemic circulation. These activated CD4+ T cells then circulate to the intestinal lamina propria, where they carry out effector functions. Abraham C, Cho JH. N Engl J Med 2009;361:

Biologic Therapy

Pathogenesis of Inflammatory Bowel Disease
Figure 1. Pathogenesis of Inflammatory Bowel Disease. Normal epithelium, with its highly evolved tight junctions and products of goblet-cell populations, most notably trefoil peptides and mucin glycoproteins, provides an effective barrier against luminal agents. The integrity of the barrier may be compromised by genetic variations in key molecular determinants, a diminished reparative response to injury, or exogenous agents, such as nonsteroidal antiinflammatory drugs. Chronic, recurrent intestinal inflammation appears to result from stimulation of the mucosal immune system by products of commensal bacteria in the lumen. Antigens from dietary sources may also contribute. Stimulation may occur as a result of the penetration of bacterial products through the mucosal barrier, leading to their direct interaction with immune cells, especially dendritic cells and lymphocyte populations, to promote a classic adaptive immune response. Alternatively, bacterial products may stimulate the surface epithelium, possibly through receptors that are components of the innate immune-response system; the epithelium can, in turn, produce cytokines and chemokines that recruit and activate mucosal immune cells. Activation of classic antigen-presenting cells, such as dendritic cells, or direct stimulation through pattern-recognition receptors promotes the differentiation of type 1 helper T cells (Th1) in patients with Crohn's disease (shown here) or, possibly, atypical type 2 helper T cells in patients with ulcerative colitis. The stereotypical products of Th1 promote a self-sustaining cycle of activation with macrophages. In addition to producing the key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage migration inhibitor factor), macrophages produce a mix of inflammatory cytokines, including interleukin-1, interleukin-6, and most notably tumor necrosis factor, which target a broad variety of other types of cells. The latter include endothelial cells, which then facilitate the recruitment of leukocytes to the mucosa from the vascular space, as well as fibroblasts and epithelium, modulating their functional properties. Most important, these functions may be altered either by genetically determined variants, as exemplified by germ-line mutations in the gene encoding NOD2, the product of the IBD1 locus, in some patients with Crohn's disease, or by environmental factors. Podolsky, D. K. N Engl J Med 2002;347:

Nielsen OH, Ainsworth MA. N Engl J Med 2013;369:754-762.
Mechanism of Therapeutic Effect of Anti–Tumor Necrosis Factor α (TNF-α) Antibodies in Inflammatory Bowel Disease. Figure 1. Mechanism of Therapeutic Effect of Anti–Tumor Necrosis Factor α (TNF-α) Antibodies in Inflammatory Bowel Disease. Anti–TNF-α antibodies bind to two types of homotrimeric TNF-α: the precursor transmembrane TNF-α (tmTNF-α) and the soluble TNF-α (sTNF-α), which is processed from tmTNF-α. Thus, these biologic agents block the interaction between TNF-α molecules and TNF-α receptor type 1 and type 2 (TNFR1 and TNFR2) as well as soluble TNF-α receptors (sTNFR), neutralizing TNF-α–mediated proinflammatory cell signaling and inhibiting the expression of inflammatory genes. Infliximab, the first TNF inhibitor on the market, is used as an example in this figure. IκB denotes inhibitor of κB, MEKK mitogen-activated protein kinase kinase, NF-κB nuclear factor κB, NIK NF-κB–inducing kinase, P phosphorylated protein, TRADD TNFR1-associated death domain protein, and TRAF TNFR-associated factor. Nielsen OH, Ainsworth MA. N Engl J Med 2013;369:

Abraham C, Cho JH. N Engl J Med 2009;361:2066-2078.
The Intestinal Immune System in Health and Disease. Figure 2. The Intestinal Immune System in Health and Disease. In healthy persons (Panel A), the lamina propria normally contains a diverse array of immune cells and secreted cytokines. These include antiinflammatory mediators (transforming growth factor β [TGF-β] and interleukin-10) that down-regulate immune responses, as well as proinflammatory mediators from both innate and adaptive immune cells that limit excessive entry of intestinal microbiota and defend against pathogens. Noninflammatory defenses, such as phagocytosis by macrophages, probably assist in defending against bacteria entering the lamina propria while minimizing tissue injury. A homeostatic balance is maintained between regulatory T cells (e.g., Treg) and effector T cells (Th1, Th2, and Th17). In persons with intestinal inflammation (Panel B), several events contribute to increased bacterial exposure, including disruption of the mucus layer, dysregulation of epithelial tight junctions, increased intestinal permeability, and increased bacterial adherence to epithelial cells. In inflammatory bowel disease, innate cells produce increased levels of tumor necrosis factor α (TNF-α), interleukin-1β, interleukin-6, interleukin-12, interleukin-23, and chemokines. There is marked expansion of the lamina propria, with increased numbers of CD4+ T cells, especially proinflammatory T-cell subgroups, which also secrete increased levels of cytokines and chemokines. Increased production of chemokines results in recruitment of additional leukocytes, resulting in a cycle of inflammation. At present, therapeutic approaches to inflammatory bowel disease (labels in red) focus on inhibiting proinflammatory cytokines, inhibiting the entry of cells into intestinal tissues (dashed arrow), and inhibiting T-cell activation and proliferation. Additional investigational biologic therapies include blockade of costimulatory signals that enhance interactions between innate cells and adaptive cells, administration of epithelial growth factors, and enhancement of tolerance through a variety of mechanisms. CD4+ Th17 cells (inset) express surface molecules such as the interleukin-23 receptor (a component of the interleukin-23–receptor complex, which consists of the interleukin-23 receptor and the interleukin-12 receptor B1) and CCR6. Interleukin-23 (comprising subunits p19 and p40) is secreted by antigen-presenting cells, and engagement of interleukin-23 with the interleukin-23–receptor complex results in activation of the Janus-associated kinase (JAK2) signal transducers and activators of transcription (STAT3), thereby regulating transcriptional activation. Interleukin-23 contributes to Th17-cell proliferation, survival, or both, and its actions are enhanced by tumor necrosis factor (ligand) superfamily, member 15 (TNFS15). Of the top 30 genetic associations with Crohn's disease, at least six genes can be implicated in Th17 cells and interleukin-23 signaling. A number of these genes are not unique to interleukin-23–Th17 signaling. Genes in the interleukin-23–Th17 pathway that have been associated with Crohn's disease are designated by red stars, and those with ulcerative colitis by blue stars. Abraham C, Cho JH. N Engl J Med 2009;361:

Vedolizumab About Biologic Infusion Targets white cells (T cells)
Prevents T-cells from moving from capillaries into surrounding tissue

T-Cell ? Activated T-Cell

T-Cell adherence Capillary T-cell

T-Cell adherence activation
Capillary T-cell

T-Cell migration Capillary T-cell

T-Cell adherence T-cell α4 β7 MAdCAM-1 Capillary

α4 β7

Original Article Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease
William J. Sandborn, M.D., Brian G. Feagan, M.D., Paul Rutgeerts, M.D., Ph.D., Stephen Hanauer, M.D., Jean-Frédéric Colombel, M.D., Bruce E. Sands, M.D., Milan Lukas, M.D., Ph.D., Richard N. Fedorak, M.D., Scott Lee, M.D., Brian Bressler, M.D., Irving Fox, M.D., Maria Rosario, Ph.D., Serap Sankoh, Ph.D., Jing Xu, Ph.D., Kristin Stephens, B.A., Catherine Milch, M.D., Asit Parikh, M.D., Ph.D., for the GEMINI 2 Study Group N Engl J Med Volume 369(8): August 22, 2013

Study Overview In this 52-week randomized trial, the α4β7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo.

Primary End Points in the Trial of Induction Therapy.
Figure 1 Primary End Points in the Trial of Induction Therapy. Panel A shows the proportions of patients who were in clinical remission and patients who had a CDAI-100 response (a decrease of 100 points or more in the score on the Crohn's Disease Activity Index [CDAI], with scores ranging from 0 to approximately 600, and with higher scores indicating greater disease activity) at week 6. Panel B shows the mean C-reactive protein (CRP) concentrations at week 0 and week 6. I bars indicate standard errors. For patients with insufficient data at the designated analysis time point, the last value was carried forward. The P value (two-sided) in Panel B was calculated with the use of the Wilcoxon rank-sum test for the change from baseline values in CRP concentrations with vedolizumab versus placebo. Sandborn WJ et al. N Engl J Med 2013;369:

End Points in the Trial of Maintenance Therapy
4 vs. 8 Week infusion Figure 2 End Points in the Trial of Maintenance Therapy. Panel A shows the proportions of patients, among those who had had clinical remission at week 6, who were still in clinical remission at week 52, who had a CDAI-100 response at week 52, and who had glucocorticoid-free remission (i.e., clinical remission without glucocorticoid therapy) at week 52 (with data for this end point available for 82 patients receiving placebo, 82 patients receiving vedolizumab every 8 weeks, and 80 patients receiving vedolizumab every 4 weeks), as well as the proportion of patients who had a durable clinical remission (defined as a clinical remission at ≥80% of study visits, including the final visit) at week 52. Panel B shows the proportions of patients who were in clinical remission from week 6 to week 52, and Panel C, the proportions of patients who had a CDAI-100 response from week 6 to week 52. Sandborn WJ et al. N Engl J Med 2013;369:

Clinical remission Figure 2 End Points in the Trial of Maintenance Therapy. Panel A shows the proportions of patients, among those who had had clinical remission at week 6, who were still in clinical remission at week 52, who had a CDAI-100 response at week 52, and who had glucocorticoid-free remission (i.e., clinical remission without glucocorticoid therapy) at week 52 (with data for this end point available for 82 patients receiving placebo, 82 patients receiving vedolizumab every 8 weeks, and 80 patients receiving vedolizumab every 4 weeks), as well as the proportion of patients who had a durable clinical remission (defined as a clinical remission at ≥80% of study visits, including the final visit) at week 52. Panel B shows the proportions of patients who were in clinical remission from week 6 to week 52, and Panel C, the proportions of patients who had a CDAI-100 response from week 6 to week 52. Sandborn WJ et al. N Engl J Med 2013;369:

CDAI-100 response Figure 2 End Points in the Trial of Maintenance Therapy. Panel A shows the proportions of patients, among those who had had clinical remission at week 6, who were still in clinical remission at week 52, who had a CDAI-100 response at week 52, and who had glucocorticoid-free remission (i.e., clinical remission without glucocorticoid therapy) at week 52 (with data for this end point available for 82 patients receiving placebo, 82 patients receiving vedolizumab every 8 weeks, and 80 patients receiving vedolizumab every 4 weeks), as well as the proportion of patients who had a durable clinical remission (defined as a clinical remission at ≥80% of study visits, including the final visit) at week 52. Panel B shows the proportions of patients who were in clinical remission from week 6 to week 52, and Panel C, the proportions of patients who had a CDAI-100 response from week 6 to week 52. Sandborn WJ et al. N Engl J Med 2013;369:

Adverse Events Affecting at Least 5% of Patients Who Received Vedolizumab.
Table 2 Adverse Events Affecting at Least 5% of Patients Who Received Vedolizumab. Sandborn WJ et al. N Engl J Med 2013;369:

Conclusions Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab.

Original Article Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis
Brian G. Feagan, M.D., Paul Rutgeerts, M.D., Ph.D., Bruce E. Sands, M.D., Stephen Hanauer, M.D., Jean-Frédéric Colombel, M.D., William J. Sandborn, M.D., Gert Van Assche, M.D., Ph.D., Jeffrey Axler, M.D., Hyo-Jong Kim, M.D., Ph.D., Silvio Danese, M.D., Ph.D., Irving Fox, M.D., Catherine Milch, M.D., Serap Sankoh, Ph.D., Tim Wyant, Ph.D., Jing Xu, Ph.D., Asit Parikh, M.D., Ph.D., for the GEMINI 1 Study Group N Engl J Med Volume 369(8): August 22, 2013

Study Overview In this 52-week randomized trial, the α4β7 integrin antibody vedolizumab was effective in treating ulcerative colitis. There were not significantly more adverse events with vedolizumab than with placebo, but the trial was not large or long enough to fully assess safety.

Exploratory Outcomes in the Trials of Vedolizumab as Induction and Maintenance Therapy
4 vs. 8 weeks Figure 1 Exploratory Outcomes in the Trials of Vedolizumab as Induction and Maintenance Therapy. Panel A shows partial Mayo Clinic scores, which range from 0 to 9, with higher scores indicating more active disease. Panel B shows scores on the Inflammatory Bowel Disease Questionnaire (IBDQ), which range from 0 to 224, with higher scores indicating a better quality of life. I bars in Panels A and B indicate standard errors. Panel C shows median fecal calprotectin concentrations. I bars indicate the interquartile range. Panel D shows the median change from week 6 in prednisone-equivalent doses. Patients receiving placebo during the trial of maintenance therapy received two doses of vedolizumab during the trial of induction therapy. For patients who withdrew early, the last observation was carried forward (Panels A, B [graph at right], C [graph at right], and D). Feagan BG et al. N Engl J Med 2013;369:

Change in IBD-Q score Figure 1 Exploratory Outcomes in the Trials of Vedolizumab as Induction and Maintenance Therapy. Panel A shows partial Mayo Clinic scores, which range from 0 to 9, with higher scores indicating more active disease. Panel B shows scores on the Inflammatory Bowel Disease Questionnaire (IBDQ), which range from 0 to 224, with higher scores indicating a better quality of life. I bars in Panels A and B indicate standard errors. Panel C shows median fecal calprotectin concentrations. I bars indicate the interquartile range. Panel D shows the median change from week 6 in prednisone-equivalent doses. Patients receiving placebo during the trial of maintenance therapy received two doses of vedolizumab during the trial of induction therapy. For patients who withdrew early, the last observation was carried forward (Panels A, B [graph at right], C [graph at right], and D). Feagan BG et al. N Engl J Med 2013;369:

Fecal calprotectin Figure 1 Exploratory Outcomes in the Trials of Vedolizumab as Induction and Maintenance Therapy. Panel A shows partial Mayo Clinic scores, which range from 0 to 9, with higher scores indicating more active disease. Panel B shows scores on the Inflammatory Bowel Disease Questionnaire (IBDQ), which range from 0 to 224, with higher scores indicating a better quality of life. I bars in Panels A and B indicate standard errors. Panel C shows median fecal calprotectin concentrations. I bars indicate the interquartile range. Panel D shows the median change from week 6 in prednisone-equivalent doses. Patients receiving placebo during the trial of maintenance therapy received two doses of vedolizumab during the trial of induction therapy. For patients who withdrew early, the last observation was carried forward (Panels A, B [graph at right], C [graph at right], and D). Feagan BG et al. N Engl J Med 2013;369:

Prednisone use Figure 1 Exploratory Outcomes in the Trials of Vedolizumab as Induction and Maintenance Therapy. Panel A shows partial Mayo Clinic scores, which range from 0 to 9, with higher scores indicating more active disease. Panel B shows scores on the Inflammatory Bowel Disease Questionnaire (IBDQ), which range from 0 to 224, with higher scores indicating a better quality of life. I bars in Panels A and B indicate standard errors. Panel C shows median fecal calprotectin concentrations. I bars indicate the interquartile range. Panel D shows the median change from week 6 in prednisone-equivalent doses. Patients receiving placebo during the trial of maintenance therapy received two doses of vedolizumab during the trial of induction therapy. For patients who withdrew early, the last observation was carried forward (Panels A, B [graph at right], C [graph at right], and D). Feagan BG et al. N Engl J Med 2013;369:

Outcome Measures at Week 6 in the Trial of Induction Therapy
Table 2 Outcome Measures at Week 6 in the Trial of Induction Therapy. Feagan BG et al. N Engl J Med 2013;369:

Outcome Measures in the Trial of Maintenance Therapy
Table 3 Outcome Measures in the Trial of Maintenance Therapy. Feagan BG et al. N Engl J Med 2013;369:

Adverse Events Affecting at Least 5% of Patients Receiving Vedolizumab in the Safety Population
Table 4 Adverse Events Affecting at Least 5% of Patients Receiving Vedolizumab in the Safety Population. Feagan BG et al. N Engl J Med 2013;369:

Conclusions Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis.

How to decide? William J. Sandborn, MD Risks and Benefits Vedolizumab
1st line Bioloigc Vedolizumab Infliximab ADA CTZ GOL Risks and Benefits William J. Sandborn, MD

William J. Sandborn, MD Feagan BG. NEJM 2013 Rutgeerts P. NEJM 2005
Sandborn WJ Gastro 2012 Sandborn WJ Gastro 2014 William J. Sandborn, MD

Efficacy of induction therapy in biologic naïve
Danese S. Annals 2014

Feagan BG. NEJM 2013 Rutgeerts P. NEJM 2005 Sandborn WJ Gastro 2012 Sandborn WJ Gastro 2014

Efficacy as first line agent in UC
Good efficacy for Induction and Maintanence therapy in UC Good efficacy for Induction and Maintanence therapy in UC Vedolizumab Anti-TNF

Sandborn WJ. NEJM 2013 Targan et al. NEJM 1997 Hanauer et al. Gastro 2006 Sandborn WJ. NEJM 2007

Sands BE. Gastro 2014

Sandborn WJ. NEJM 2013 Sandborn WJ. NEJM 2007 Colombel et al. Gastro 2007 Hanauer et al. Lancet 2002

Efficacy as first line agent
Good efficacy for Induction and Maintanence therapy in UC and CD Good efficacy for Induction and Maintanence therapy in UC and CD Vedolizumab Anti-TNF

Feagan BG. NEJM 2013 Sandborn WJ NEJM 2013

Prior biologic use Efficacy of subcutaneous biologics impacted by prior biologic exposure Impact of prior biologic exposure on efficacy of Infliximab less clear Chaparro M WJG 2012

Efficacy as first line agent
Good efficacy for Induction and Maintanence therapy in UC and CD Prior biologics WILL impact efficacy Good efficacy for Induction and Maintanence therapy in UC and CD Prior biologics MAY impact efficacy Vedolizumab Anti-TNF Sandborn

Black Box Warnings Vedolizumab Ant-TNF Serious Infections None
Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens. Malignancy Lymphoma and other malignancies Fatal hepatosplenic T-cell lymphoma

(Vedolizumab, Natalizumab)
Lymphoma risk Lymphoma Expected Rate (General Population) 2/10,000 PYF Anti-TNF therapy 6/10,000 PYF Anti-integrins (Vedolizumab, Natalizumab) 3/10,000 PYF Dulai PS, Siegel CA. GCNA 2014

Dermatology (psoriasis)
Other Risks Vedolizumab Anti-TNF therapy Serious Infection - +/- Opportunistic + Demyelinating Autoimmune (SLE, vasculitis) Dermatology (psoriasis) Cardiac (CHF) Pulmonary (Sarcoidosis, ILD) Caveat: most new drugs have additional toxicities identified during post-marketing surveillance Kopylov U. GCNA 2014 Feuerstein JD. GCNA 2014

Risks of Therapy Anti-TNF Vedolizumab
Good efficacy for Induction and Maintanence therapy in UC and CD Prior biologics WILL impact efficacy Low risk of malignancy, driven by IMM No signal for systemtic risks Good efficacy for Induction and Maintanence therapy in UC and CD Prior biologics MAY impact efficacy Low risk of malignancy, driven by IMM Systemtic risks well established Vedolizumab Anti-TNF

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