Takeda Obtains New Drug Application Approval for Entyvio ® (vedolizumab) for the Treatment of Ulcerative Colitis in Japan

-New treatment option for patients with moderately to severely active ulcerative colitis in Japan

Osaka, Japan, July 2, 2018 --- Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that it has obtained a New Drug Application Approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for Entyvio (generic name: vedolizumab, development code: MLN0002) for the treatment of patients with moderately to severely active ulcerative colitis (UC) in Japan.

Takeda submitted a New Drug Application to the MHLW in August 2017 based on the results from Study CCT-101, a Phase 3 clinical study including Japanese patients with moderately to severely active UC alongside data from the global GEMINI 1 pivotal Phase 3 clinical study of vedolizumab induction and maintenance treatment involving 895 patients with moderately to severely UC.

“In recent years, the number of patients with UC in Japan has been on the increase. The quality of medical treatment has improved and more treatment options are available, but many patients continue to experience difficulty in their daily lives,” said Dr. Toshifumi Hibi, Director of the Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital. “I believe that the addition of Entyvio to available treatment options, as a new biologic treatment for UC with a novel mechanism of action that selectively inhibits the migration of inflammatory cells in the digestive tract, represents a major step forward in the treatment of UC by bringing us closer to achieving better long-term treatment goals.”

“Entyvio has been approved in more than 60 countries worldwide and has provided a major step forward in helping patients with UC achieve and maintain clinical remission. I am delighted that we are now able to offer this new treatment option to patients in Japan,” said Naoyoshi Hirota, Head of the Takeda Development Center Japan. “The recent approval of Takeda’s New Drug Application represents a major milestone for Takeda. We aspire to bring better health and a brighter future for people worldwide through the delivery of innovative and life-changing medicines.”

Entyvio was approved in the European Union and the U.S. in May 2014 for the treatment of adults with moderately to severely active UC or Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNFα antagonist. As of May 2018, global post-marketing exposure to Entyvio totals more than 200,000 patient-years.

About the CCT-101 Study
The CCT-101 study included 292 Japanese patients with moderately to severely active UC. In Cohort 1 of the induction phase, 246 patients were randomized to receive investigational vedolizumab 300 mg or placebo at weeks 0, 2 and 6, using the double-blind method. In Cohort 2 of the induction phase, 46 patients received open-label vedolizumab 300 mg at weeks 0, 2 and 6. After the efficacy evaluation at week 10, patients showing a clinical response to vedolizumab entered the maintenance phase at week 14 and were randomized to receive investigational vedolizumab 300 mg or placebo every eight weeks until week 54.

At week 10, there was a numerically higher clinical response rate, the primary endpoint of the induction phase, seen with the investigational vedolizumab group (39.6%) versus the placebo group (32.9%) during induction (P=0.2722: adjusted odds ratio [AOR] =1.37; 95% CI, 0.779-2.399), though the difference was not statistically significant. At week 60, the clinical remission rate, the primary endpoint of the maintenance phase, was 56.1% (23/41) versus 31.0% (13/42) for patients receiving investigational vedolizumab and placebo, respectively, with this difference being statistically significant (P=0.0210; AOR=2.88; 95% CI, 1.168-7.108). Furthermore, treatment-emergent adverse events were generally mild-to-moderate with no clinically significant safety differences observed between the treatment groups.

About GEMINI 1
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.

GEMINI 1 is a phase 3 randomized, double-blind, placebo-controlled study, to compare vedolizumab induction (week 6) and maintenance (week 52) treatment with placebo in 895 patients with moderately to severely active UC, despite treatment with at least one conventional therapy or TNFα-antagonist therapy.

At week 6, a greater percentage of patients receiving vedolizumab achieved clinical response compared to placebo, 47.1% vs. 25.5%, respectively (95% confidence interval (CI), 11.6-31.7; p<0.001). At week 52, a greater percentage of patients receiving vedolizumab every 4 weeks achieved clinical remission compared to placebo, 44.8% vs. 15.9% for placebo (95% CI, 17.9-40.4; p<0.001). Similar findings were observed in the group receiving vedolizumab every 8 weeks, 41.8% vs. 15.9% for placebo (95% CI, 14.9-37.2; p<0.001). No important safety differences were observed among the study groups in the most commonly reported adverse events. Serious infections were not more common with vedolizumab than with placebo. No cases of PML occurred.

About ulcerative colitis
Ulcerative colitis is one of the most common forms of inflammatory bowel disease (IBD), affecting over 220,000 people[1] in Japan. UC is a chronic, relapsing, remitting, inflammatory condition of the gastrointestinal (GI) tract that is often progressive in nature. UC involves the innermost lining of the large intestine and often presents with symptoms of abdominal discomfort and loose bowel movements, including blood or pus. The cause of UC is not fully understood, but recent research suggests hereditary, genetic, and environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to UC.

About Entyvio
Entyvio (vedolizumab) is a prescription medicine that has been approved for adults with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) in more than 60 countries worldwide. In people with UC, there are an increased number of inflammatory white blood cells entering the mucosal lining of the bowel. The presence of these inflammatory cells can lead to the symptoms most commonly seen in people who have UC. Entyvio is designed to reduce this inflammation by blocking the movement of the white blood cells into the inflamed gut tissue. Mucosal addressing cell adhesion molecule 1 (MAdCAM-1) is preferentially expressed on the endothelial lining of blood vessels in the lymphoid tissue of the bowel. The alpha 4 beta 7 integrin is expressed on a subset of circulating white blood cells. Entyvio specifically binds to the alpha4beta7 integrin and blocks its interaction with MAdCAM-1, therefore inhibiting the white blood cells from entering the inflamed gut tissue, thus decreasing inflammation.

Takeda’s Commitment to Gastroenterology
More than 70 million people worldwide are impacted by gastrointestinal (GI) diseases, which can be complex, debilitating and life-changing. Takeda is driven to improving the lives of patients with GI diseases through innovative medicines, dedicated patient disease management support and the evolution of the healthcare environment. Takeda is at the forefront of the field of GI in delivering innovative medicines in areas that are associated with high unmet needs, including inflammatory bowel disease, acid-related diseases and motility disorders. Our GI research and development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies. With more than 25 years of experience in this area, our broad approach to treating the many diseases that impact the GI system, and our global network of collaborators, Takeda aims to contribute to advances in the ways in which patients manage their disease.

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology,

_{^{[1] The total of people granted medical claimant and/or registration certificates (for the treatment of UC) in 2013 (Japan Intractable Diseases Information Center website)}}

gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.

An overview of Entyvio

Brand name	Entyvio® for I.V. Infusion 300mg.
Generic name	Vedolizumab [Genetical Recombination]
Effects / Indications	Treatment and maintenance therapy for moderate to severe ulcerative colitis (The drug should be used only in patients with inadequate response to conventional treatment.)
Dosage / Administration	The usual adult dose of vedolizumab (genetical recombination) for intravenous infusion is 300 mg/dose. The drug should be administered at Week 2 and 6 after the initial administration and at 8-week intervals thereafter.

Disclaimer
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.

---

Media Contacts
Ryoko Omichi
Media in Japan
Communications Department
Japan Pharma Business Unit
Takeda Pharmaceutical Company Limited
Tel: 03-3278-2665   Email:　< [email protected]>

Luke Willats
Media outside of Japan
T: +41 44 555 1145
[email protected]