Five-Year Open-Label Prospective Study Data Presented at the 12th Congress of European Crohn's and Colitis Organisation (ECCO) Provides Information on the Long-Term Use of Vedolizumab in Adult Patients with Moderate to Severely Active Ulcerative Colitis and Crohn's Disease

Post-hoc data from GEMINI I also presented at ECCO further support a favorable benefit: risk profile for vedolizumab as a treatment option for adult patients with moderate to severely active ulcerative colitis to maintain sustained remission

OSAKA, Japan, Feb. 17, 2017 /PRNewswire/ -- Takeda Pharmaceutical Company Limited [TSE: 4502], ("Takeda") today announced that interim findings from the ongoing, open-label GEMINI long-term safety (LTS) study were presented during the 12^th Congress of European Crohn's and Colitis Organisation (ECCO) in Barcelona, Spain, February 15-18, 2017. Data presented from two five-year interim analyses of effectiveness and safety in patients with moderate to severely active ulcerative colitis (UC) and Crohn's disease (CD) indicated that long-term treatment of vedolizumab in responders was associated with long-term clinical response and remission, in addition to health-related quality of life (HRQL) improvements for patients over a five-year period.

The LTS study is an ongoing open-label prospective study investigating the long-term safety of vedolizumab in moderate to severely active inflammatory bowel disease (IBD). One hundred and forty six patients with CD were enrolled from GEMINI II and 154 patients with UC were enrolled from GEMINI I. This interim analysis reports clinical effectiveness evaluated at five years. Fifty-eight patients with CD and 54 patients with UC had discontinued therapy before the data cut-off (11 [19%] and 19 [35%] patients discontinuing respectively, due to lack of benefit). Twenty-seven CD patients and 37 UC patients had not reached the five-year assessment time point in the study. Sixty-one patients with CD and 63 patients with UC were evaluated in the analysis. Patients with CD were assessed for clinical response (decrease in Harvey–Bradshaw Index [HBI] of ≥3 points from baseline [BL]). Clinical remission was defined as HBI ≤4. Patients with UC were assessed for clinical response (decrease in partial Mayo score [PMS] of ≥2 points and ≥25% change from BL, with an accompanying decrease in rectal bleeding subscore of ≥1 point from BL or absolute rectal bleeding subscore of ≤1 point). Clinical remission was defined as PMS of ≤2 with no individual subscore >1. This interim analysis showed that for the 63 observed patients with moderate to severely active UC, 98% experienced clinical response, and 90% were in clinical remission after five years of continued vedolizumab treatment. For the 61 observed patients with moderate to severely active CD, 95% experienced clinical response and 89% were in clinical remission after five years of continued vedolizumab treatment. Long-term use of vedolizumab was also associated with improvements in HRQL, which was measured by IBD Questionnaire (IBDQ) and Euro Quality of Life-5D visual analogue scale (EQ-5D VAS). The safety profile was consistent with that previously observed in a three-year interim analysis of the LTS study in patients with moderate to severely active UC and CD.

"These latest findings underscore the consistent safety profile and effectiveness of vedolizumab as a long-term treatment option for adults with moderate to severely active ulcerative colitis and Crohn's disease," said Prof. Dr. Severine Vermeire, University Hospitals Leuven, Belgium. "It is encouraging that the data continue to show the potential benefit of vedolizumab use for people impacted by one of these two chronic diseases."

Additional data from a post-hoc analysis of GEMINI I reported vedolizumab (n=620) was significantly more effective than placebo (n=149) at achieving sustained remission, defined as clinical remission (PMS ≤2 points with no individual subscore >1 point) and rectal bleeding subscore equaling 0 at weeks 26, 38 and 52, in patients with moderate to severely active UC who achieved remission at week 14. The analysis included patients enrolled in GEMINI I, who responded to two induction doses of vedolizumab and entered 46 weeks of maintenance therapy with either placebo or vedolizumab. Maintenance treatment with vedolizumab resulted in 60% of patients sustaining clinical remission from week 14 to week 52 compared with 37% who underwent placebo washout.

Findings from real-world data are an important supplement to randomized controlled studies when evaluating the clinical effectiveness and safety of vedolizumab in patients with moderate to severely active UC and CD. In a systematic review and meta-analysis, MEDLINE-, Cochrane-, and Embase-indexed publications and conference abstracts (n ≥10) were searched from May 1, 2014-October 31, 2016 for studies reporting real-world effectiveness of vedolizumab. A total of 98 studies were identified with 20 cohorts on response and remission outcomes in 1,714 patients (UC: 703; CD: 1,010) over a one-year treatment period. Most vedolizumab patients (≥71%) had prior exposure to ≥1 anti-tumour necrosis factor (TNF) therapy. Outcome measures included PMS, Simple Clinical Colitis Activity Index, HBI, Crohn's Disease Activity Index and Physician Global Assessment. The pooled real-world clinical response and remission rates and safety data supported a favorable benefit: risk profile of vedolizumab in patients with UC and CD.

Takeda is committed to the ongoing study of vedolizumab for moderate to severely active UC and CD, with the goal of continuing to support the patient and professional communities. A total of six oral and 15 poster presentations were presented at the 12^th Congress of ECCO, including additional post-marketing surveillance and real-word safety data, further demonstrating a consistent safety profile of long-term vedolizumab treatment in patients living with moderate to severely active UC and CD.

About Ulcerative Colitis and Crohn's Disease
Ulcerative colitis (UC) and Crohn's disease (CD) are marked by inflammation in the gastrointestinal tract. UC impacts the large intestine only, which includes the colon and the rectum. The most common symptoms of UC include abdominal discomfort and blood or pus in diarrhea. CD can impact any part of the digestive tract and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and fever. There is no known cause for UC or CD, although many researchers believe that the interaction between genes, the body's immune system, and environmental factors play a role. The aim of UC and CD treatments is to induce and maintain remission, or achieve extended periods of time when patients do not experience symptoms.

About Entyvio (vedolizumab) 
Vedolizumab, developed for the treatment of UC and CD, is a humanized monoclonal antibody that is designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and fibronectin, 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. These cells have been shown to play a role in mediating the inflammatory process in UC and CD.  By inhibiting alpha4beta7, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.

Therapeutic indications

Ulcerative colitis
Vedolizumab is indicated for the treatment of adult patients with moderate 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.

Crohn's disease
Vedolizumab is indicated for the treatment of adult patients with moderate 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.

Important Safety Information

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use
Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering vedolizumab. Observe patients during infusion and until the infusion is complete.

Infusion-related reactions
In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks.

Infections
Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity. Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier. Vedolizumab treatment is not to be initiated in patients with active, severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment. Before starting treatment with vedolizumab, screening for tuberculosis may be considered according to local practice. Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut-homing lymphocytes, vedolizumab exerts an immunosuppressive effect on the gut. Although no systemic immunosuppressive effect was noted in healthy subjects, the effects on systemic immune system function in patients with inflammatory bowel disease patients is not known. No cases of PML were reported in clinical studies of vedolizumab however, healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms, and consider neurological referral if they occur. If PML is suspected, treatment with vedolizumab must be withheld; if confirmed, treatment must be permanently discontinued. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months.

Malignancies
The risk of malignancy is increased in patients with ulcerative colitis and Crohn's disease. Immunomodulatory medicinal products may increase the risk of malignancy.

Prior and concurrent use of biological products
No vedolizumab clinical trial data are available for patients previously treated with natalizumab. Caution should be exercised when considering the use of vedolizumab in these patients. No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. Therefore, the use of vedolizumab in such patients is not recommended.

Vaccinations
Prior to initiating treatment with vedolizumab all patients should be brought up to date with all recommended immunizations. Patients receiving vedolizumab may receive non-live vaccines (e.g., subunit or inactivated vaccines) and may receive live vaccines only if the benefits outweigh the risks.

Adverse Reactions include: Nasopharyngitis, Bronchitis, Upper respiratory tract infection, Influenza, Sinusitis, Headache, Oropharyngeal pain, Cough, Nausea, Rash, Pruritus, Arthralgia, Back pain, Pain in extremities, and Pyrexia.

Please consult with your local regulatory agency for approved labeling in your country.

For U.S. audiences, please see the full Prescribing Information including Medication Guide for ENTYVIO.

For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO.

Takeda's Commitment to Gastroenterology
Takeda is a global leader in gastroenterology. With expertise spanning more than 25 years, the company's dedication to innovation continues to evolve and have a lasting impact. ENTYVIO® (vedolizumab) demonstrates Takeda's global capabilities and expansion into the specialty care market in gastroenterology and biologics. Designed and developed specifically to target the gastrointestinal (GI) tract, ENTYVIO was launched in 2014 for the treatment of adults with moderate to severe ulcerative colitis and Crohn's disease. TAKECAB® (vonoprazan fumarate) is Takeda's potassium-competitive acid blocker and was launched in Japan in 2015. Takeda also markets motility agent AMITIZA® (lubiprostone), which originally launched in 2006 for the treatment of chronic idiopathic constipation, and received subsequent approval to treat irritable bowel syndrome with constipation and opioid-induced constipation. Preceding these notable launches, Takeda pioneered gastroenterological breakthroughs in proton pump inhibitors beginning in the 1990's with lansoprazole. Through specialized and strategic in-house development, external partnerships, in-licensing and acquisitions, Takeda currently has a number of promising early stage GI assets in development, and remains committed to delivering innovative, therapeutic options for patients with gastrointestinal and liver diseases.

About Takeda Pharmaceutical Company 
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.