Takeda Highlights Favorable Safety Profile of Entyvio^® (vedolizumab) Through Comparative Real-World Data Versus TNFα-Antagonist Therapy in Ulcerative Colitis and Crohn’s Disease

Osaka, Japan, June 3, 2018 – Takeda Pharmaceutical Company Limited [TSE:4502] (“Takeda”) today announced a new analysis of real-world data comparing the safety data of the gut-selective biologic Entyvio^® (vedolizumab) and tumor necrosis factor-alpha (TNFα)-antagonist therapy. The results showed numerically lower rates of serious infections (SIs) [6.9% vs 10.1%; odds ratio (OR) 0.67, 95% confidence interval (CI) 0.41-1.07] and significantly lower rates of serious adverse events (SAEs) [7.1% vs 13.1%; OR 0.51, 95% CI 0.32-0.81] in patients treated with Entyvio (n=436) compared to TNFα-antagonist therapy (n=436). This analysis of the VICTORY (Vedolizumab Health OuTComes in InflammatORY Bowel Diseases) Consortium evaluated the occurrence of adverse events (AEs) in patients with ulcerative colitis (UC) and Crohn’s disease (CD) who received vedolizumab compared with TNFα-antagonist therapy and was presented as an oral presentation at the 2018 Digestive Disease Week^® (DDW) annual scientific meeting held from June 2-5 in Washington, D.C.

Data from 872 UC and CD patients (n=334 UC, n=538 CD; n=436 Entyvio; 47% male, median age 35 years), from the UC and CD VICTORY Consortium database, were analyzed to compare the safety of Entyvio to TNFα-antagonist therapy. Patients receiving Entyvio were matched (1:1)* to patients on TNFα-antagonist therapy using propensity scores to control for baseline differences between groups. Among patients on biologic monotherapy (n=247; n=142 Entyvio), Entyvio-treated patients were observed to have numerically lower rates of SIs (4.1% vs 10.1%; OR 0.37, 95% CI 0.13-1.02) and significantly lower rates of SAEs (4.7% vs 14.5%; OR 0.29, 95% CI 0.12-0.73). Among patients who were on biologic therapy in combination with both steroids and an immunomodulator (n=137; n=69 Entyvio), rates of SIs (11.5% vs 13.9%, OR 0.81, 95% CI 0.31-2.07) and SAEs (14% vs 14%, OR 0.66, 95% CI 0.27-1.65) were similar between Entyvio and TNFα-antagonist treated patients.Concomitant immunosuppressive use was associated with an increased risk for both SI and SAE, and rates were similar between Entyvio and TNFα-antagonist therapy when using concomitant immunosuppressive therapy.**

“As we add to the extensive body of real-world evidence supporting the safety profile of Entyvio, it is encouraging to see the lower rates of serious infections and adverse events as compared to TNFα-antagonist therapy in this rigorous analysis,” said Parambir Dulai, M.D., Research Fellow, University of California San Diego, and Lead Investigator of the VICTORY Consortium analyses. “Further studies will seek to understand the potential impact of gut-selective treatment versus systemic immunosuppression on clinical safety in the real world.”

Further safety analyses from the GEMINI studies, also presented at DDW, support the safety profile of Entyvio. Results from a post-hoc analysis of interim data from the GEMINI long-term safety study (n=421; UC 190; CD 231) show nearly two-thirds of patients with UC (64%) and more than half with CD (55%) persisted with Entyvio treatment for three years, with low rates of discontinuation due to AEs, and treatment persistence rates higher in patients without versus with prior TNFα-antagonist failure (UC p=0.18: 69% vs 61%; CD p<0.01: 68% vs 51%). In addition, the GEMINI open-label extension (OLE) study showed that patients who were TNFα-antagonist therapy naïve experienced significantly fewer AEs (94 vs 275 per 100 patient-years) and SAEs (10 vs 18 per 100 patient-years) compared to TNFα-antagonist -experienced patients. Data from the GEMINI post-marketing (PM) setting were also analyzed and reported that a similar number of patients reported AEs in both groups, but limitations of PM safety reports, including incomplete data, must be considered when interpreting these results.

“Long-term remission and a well-established safety profile are key factors when it comes to treating chronic conditions like UC and CD,” said Karen Lasch, M.D., Medical Head, GI Specialty, U.S. Medical Office, Takeda. “We are grateful for the work of groups like the VICTORY Consortium and pleased that results from multiple studies continue to support the safety and effectiveness of Entyvio.”

For a full list of poster titles and authors at this year’s DDW meeting visit, http://www.ddw.org/attendee-planning/online-planner.

*Propensity score matching (1:1) accounting for age, sex, prior disease-related hospitalization within the previous year, disease phenotype (stricturing or penetrating complication history for CD, disease extent for UC), disease severity, prior bowel surgery for CD, steroid refractoriness or dependence, and prior TNFα-antagonist failure.

** Rates of SIs and SAEs were compared using logistic regression analyses between matched patients; SIs were defined as requiring antibiotics or hospitalization or resulting in discontinuation or death, and SAEs as SI or non-infectious adverse events resulting in discontinuation or death.

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About Entyvio^® (vedolizumab)

Vedolizumab is a gut-selective immunosuppressive biologic.It is a humanized monoclonal antibody that is designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin 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 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.

About the VICTORY Consortium

The VICTORY (Vedolizumab Health OuTComes in InflammatORY Bowel Diseases) Consortium is a collaboration currently comprised of 16 leading inflammatory bowel disease (IBD) centers from across the U.S. and represents the first large, well-characterized cohort of patients taking Entyvio^® in a real-world setting in the U.S. Patients included in the consortium were identified at each site through electronic medical record searches, review of clinical records, and/or queries of infusion center records. More than 1,700 UC and CD patients are now included in the consortium database, which was started when Entyvio^® was launched in the U.S. in 2014.

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 (GI) 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. UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus. CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss. 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.

Therapeutic Indications

Ulcerative colitis

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.

Crohn’s disease

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.

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 equipped 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 all 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 are 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, Headache, Arthralgia, Upper respiratory tract infection, Bronchitis, Influenza, Sinusitis, Cough, Oropharyngeal pain, Nausea, Rash, Pruritus, Back pain, Pain in extremities, Pyrexia, and Fatigue.

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

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.

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, 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. Around 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/.

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