Investigational Subcutaneous Formulation of Vedolizumab Meets Primary Endpoint in Achieving Clinical Remission at Week 52 in Patients with Moderately to Severely Active Crohn's Disease
Osaka, Japan, July 22, 2019 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced top-line results from the VISIBLE 2 clinical trial evaluating the efficacy and safety of an investigational subcutaneous (SC) formulation of the gut-selective biologic vedolizumab as maintenance therapy in adult patients with moderately to severely active Crohn's disease (CD) who achieved clinical response* at week 6 following two doses of open-label vedolizumab intravenous (IV) therapy at weeks 0 and 2.
 In evaluating the primary endpoint of the trial, a statistically significant proportion of patients receiving vedolizumab SC achieved clinical remission** at week 52 compared to placebo. Patients received vedolizumab SC beginning at week 6 and every 2 weeks up to week 50.1 Adverse events were consistent with the known safety profile of vedolizumab IV, and no new signals were identified.
“Meeting the primary endpoint of the VISIBLE 2 study marks a crucial step in our efforts to help patients with Crohn’s disease as to how they may receive treatment with vedolizumab, whether that is intravenously or subcutaneously. These data, alongside the pivotal VISIBLE 1 results in ulcerative colitis, provide a more comprehensive picture of the new investigational subcutaneous formulation of vedolizumab as maintenance therapy for both ulcerative colitis and Crohn’s disease,” said Asit Parikh, MD PhD, Head of Takeda’s Gastroenterology Therapeutic Area Unit.
These results will be shared with regulatory authorities and further data from the VISIBLE 2 trial will be presented at a future scientific congress. The subcutaneous formulation of vedolizumab forms part of Takeda’s ongoing commitment to meet the individual preferences of patients worldwide.
VISIBLE 2 is a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of vedolizumab SC as maintenance therapy in patients with moderately to severely active CD.1 The study enrolled 644 participants, all of whom had an inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or tumor necrosis factor-alpha (TNFα)-antagonist therapy prior to being enrolled.1 Patients who achieved clinical response at week 6 (n=410), following two doses of open-label vedolizumab 300 mg IV therapy at weeks 0 and 2, were randomized into one of two treatment groups, vedolizumab 108 mg SC or placebo SC.1 Both treatment groups received a subcutaneous injection every two weeks starting at week 6 up to week 50.1
* Clinical response is defined as a ≥70 point decrease in Crohn's Disease Activity Index (CDAI) score from baseline (week 0).2
** Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score ≤150 at week 52.1
About the VISIBLE Clinical Trial Program
The VISIBLE clinical trial program aims to assess the efficacy and safety of an investigational subcutaneous (SC) formulation of vedolizumab as maintenance therapy in adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD).1,,
VISIBLE consists of three phase 3 studies involving over 1,000 UC and CD patients which includes two randomized, double-blind, placebo-controlled studies examining the proportion of patients achieving clinical remission at week 52, and an open-label extension study to determine the long-term safety and efficacy of vedolizumab SC.1,3,4
About Ulcerative Colitis and Crohn’s Disease
Ulcerative colitis (UC) and Crohn’s disease (CD) are two of the most common forms of inflammatory bowel disease (IBD). Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract that are often progressive in nature., UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus., CD can also affect the entire thickness of the bowel wall, while UC only involves the innermost lining of the large intestine.7,8 UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus.8, CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.6 The cause of UC or CD is not fully understood; however, recent research suggests hereditary, genetics, environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to UC or CD.8,,
About Entyvio® (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation., It is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.15 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).15,, By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.15
Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active UC and CD, who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα)-antagonist.13,14 Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 330,000 patient years of exposure to date.2
Therapeutic Indications (vedolizumab IV)
Vedolizumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.
Vedolizumab is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNFα) antagonist.
 Efficacy and safety of vedolizumab subcutaneous (SC) as maintenance therapy in Crohn's disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02611817. Last updated: June 17, 2019. Last accessed: July 2019.
 Takeda Data on File. 2019.
 Efficacy and safety of vedolizumab subcutaneously (SC) as maintenance therapy in ulcerative colitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02611830. Last updated: August 27, 2018. Last accessed: July 2019.
 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.
 Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605.
 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363.
 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.
 Feuerstein JD, Cheifetz AS. Crohn’s disease: Epidemiology, diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103.
 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.
 Henckaerts L, Pierik M, Joossens M, et al. Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut. 2007;56:1536-1542.
 Kaser A, Zeissig S, Blumberg RS. Genes and environment: How will our concepts on the pathophysiology of IBD develop in the future? Dig Dis. 2010;28:395-405.
 European Medicines Agency. Entyvio EPAR product information. EMEA/H/C/002782 - IB/0030 ANNEX 1 Summary of Product Characteristics. Available at: https://www.ema.europa.eu/documents/product-information/entyvio-epar-product-information_en.pdf. Last updated: April 1, 2019. Last accessed: July 2019.
 Soler D, Chapman T, Yang LL, et al. The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-875.
 Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151:97‑110.
 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312.
 Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis. 2016;10:1437-1444.