Osaka, Japan, May 22, 2019 --- Takeda Pharmaceutical Company Limited ("Takeda") (TSE: 4502/NYSE: TAK) today announced that it has obtained approval from the Ministry of Health, Labour and Welfare (MHLW) for an additional indication for Entyvio® (generic name: vedolizumab, development code: MLN0002) for the treatment of adult patients with moderately to severely active Crohn's disease (CD) in Japan. Entyvio was also approved in Japan in July 2018 for the treatment of adult patients with moderately to severely active ulcerative colitis with the medicine launched in November 2018.
The application filing submitted to the MHLW in July 2018 included data from Study CCT-001, a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 clinical trial investigating the efficacy, safety and pharmacokinetics of vedolizumab induction and maintenance treatment involving 157 Japanese patients with moderately to severely active CD, in addition to data from the global GEMINI 2 and 3 trials involving 1,115 and 416 patients respectively.1,2,3
Dr. Takanori Kanai, Professor of Gastroenterology and Hepatology at Keio University said, "Crohn's disease is an inflammatory bowel disease along with ulcerative colitis. The number of patients with Crohn's disease in Japan is rapidly increasing, and many patients experience difficulties in their daily lives from this chronic disease. Entyvio is a biologic medicine with a new mechanism of action that regulates the immune response selectively in the gut and was approved last year in Japan as a new treatment option for ulcerative colitis. This approval means there is now another option that can help contribute to the solution of unmet needs in the treatment of Crohn's disease."
Naoyoshi Hirota, Director of the Japan Development Center, said, "Entyvio has been approved in more than 60 countries worldwide and has been contributing to the induction and maintenance of clinical remission of patients with ulcerative colitis since last year in Japan. I am proud that we can now offer Entyvio as a treatment option for patients with Crohn's disease in Japan. The addition of this indication is an important milestone for Takeda. We will continue our efforts to improve the lives of patients through innovative medicines."
About Crohn's Disease
It is estimated that there are currently over 40,000 patients suffering from Crohn's disease (CD) in Japan.4 CD is one of the most common inflammatory bowel diseases and is characterized by chronic, relapsing, remitting, inflammation that may have skip lesions mainly in the small and large intestine.5,6 Common symptoms are diarrhea, abdominal pain, fever, weight loss, and malnutrition.6 Although the exact cause of CD remains unclear, recent research suggests that several factors may play a part, including genetic predisposition, environmental factors, and abnormal immune response to intestinal bacterial antigens.7,8,9
About the CCT-001 Trial
CCT-001 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial investigating the efficacy of vedolizumab induction and maintenance treatment involving 157 Japanese patients with moderately to severely active Crohn's disease (CD).1
In the induction phase, which included a verification analysis, the double-blind method was used to randomly assign patients to a group receiving vedolizumab 300 mg at week 0, 2, and 6 or placebo. Patients who showed improvement (CDAI-70 improvement: CDAI score decreased by 70 points or more from baseline) following administration of vedolizumab at the week 10 evaluation of efficacy were included in the maintenance period at Week 14 and were randomly assigned to receive either vedolizumab 300 mg or placebo every 8 weeks until Week 54. The maintenance phase was not designed to examine statistical validity of efficacy, but to determine whether the results were similar to those obtained in previous studies conducted worldwide.
The vedolizumab group exceeded the placebo group (26.6% vs. 16.7%) in terms of the percentage of CDAI-100 improvement (≥100-point decrease in the CDAI score), which was a primary endpoint of the induction period, however the difference was not statistically significant [p = 0.1448; adjusted odds ratio (AOR) = 1.80; 95% CI, 0.816-3.958]. The proportion of patients in remission at Week 60 (CDAI score less than 150 points), which was a primary endpoint, were 41.7% in the vedolizumab group and 16.7% in the placebo group. Primary and secondary endpoint results in the induction and maintenance period showed broadly the same trends as seen in the GEMINI II and III trials.2,3 In addition, adverse events were generally mild to moderate, and there were no clinically significant differences between treatment groups regarding safety.10
About the GEMINI Studies
The safety and efficacy of vedolizumab is supported by the results of the GEMINI clinical trial program. These phase 3 studies involved 2,400 individuals with ulcerative colitis (UC) or Crohn's disease (CD) who were recruited from nearly 40 countries.11,12,13
The GEMINI program consists of four studies - a placebo-controlled study of vedolizumab induction and maintenance treatment in patients with moderately to severely active UC (GEMINI 1), a placebo-controlled study of vedolizumab induction and maintenance treatment in patients with moderately to severely active CD (GEMINI 2), a placebo-controlled study of vedolizumab induction in patients with moderately to severely active CD (GEMINI 3) and an open-label long-term safety study of vedolizumab in patients with either CD or UC (GEMINI long-term safety).11,12,13,14
About Entyvio® (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.15 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).16 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.17 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.16 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn's disease (CD).16,18,19 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.16
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.15 Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 260,000 patient years of exposure to date.20
Takeda's Commitment to Gastroenterology
Gastrointestinal (GI) diseases can be complex, debilitating, and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for over 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies.
The drug information contained herein is intended for the disclosure of Takeda corporate information and is not intended to advertise or promote any prescription drug, including those under development.
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1 Phase III Study of MLN0002 (300 mg) in Treatment of Crohn's Disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02038920. Last updated: April 25, 2019. Last accessed: May 2019.
2 Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369,711-721.
3 Sands BE, Feagan BG, Rutgeerts P, at 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.
4 Japan Intractable Diseases Information. Total people granted medical claim and/or registration certificates (for the treatment of CD) in 2016
5 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.
6 Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012;380:1590-1605.
7 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.
8 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.
9 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.
10 Ogata H, Motoya S, Watanabe K, et al. A phase 3 study of vedolizumab for induction and maintenance therapy in Japanese patients with moderate to severe Crohn's disease. Gastroenterology. 2019;156(Issue 6):S1109.
11 Study of vedolizumab (MLN0002) in patients with moderate to severe ulcerative colitis (GEMINI I). Available at: https://clinicaltrials.gov/ct2/show/NCT00783718. Last updated: July 18, 2014. Last accessed: May 2019.
12 Study of vedolizumab (MLN0002) in patients with moderate to severe Crohn's disease (GEMINI II). Available at: https://clinicaltrials.gov/ct2/show/NCT00783692. Last updated: July 21, 2014. Last accessed: May 2019.
13 Study of vedolizumab in patients with moderate to severe Crohn's disease (GEMINI III). Available at: https://clinicaltrials.gov/ct2/show/NCT01224171. Last updated: July 21, 2014. Last accessed: May 2019.
14 An open-label study of vedolizumab (MLN0002) in participants with ulcerative colitis and Crohn's disease (GEMINI LTS). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT00790933 Last updated: March 12, 2019. Last accessed: May 2019.
15 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. Last updated: February 2018. Last accessed: April 2019.
16 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.
17 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.
18 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312.
19 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.
20Takeda Data on File. 2019.
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