Additional Interim Data Supporting Long-Term Use of Vedolizumab in Patients with Ulcerative Colitis and Crohn's Disease Published in Journal of Crohn's and Colitis

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OSAKA, Japan, Sept. 28, 2016 /PRNewswire/ -- Takeda Pharmaceutical Company Limited [TSE: 4502], ("Takeda") announced that two interim reports from the ongoing, open-label GEMINI long-term safety (LTS) study describing clinical data of long-term Entyvio (vedolizumab) treatment in patients with moderately to severely active ulcerative colitis (UC) and moderately to severely active Crohn's disease (CD) have been published in the Journal of Crohn's & Colitis.

The data showed that patients with moderately to severely active UC experienced clinical and health-related quality of life (HRQL) improvements with continued vedolizumab treatment. For patients with moderately to severely active CD, the clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. UC and CD patients that entered the study after discontinuing prior eight-weekly maintenance dosing due to loss of clinical response, in GEMINI I and II respectively, could experience a beneficial effect with increasing dosing frequency to every four weeks.

GEMINI LTS is an ongoing, single-arm, open-label phase 3 extension study, with a primary objective of evaluating the safety profile of long-term vedolizumab treatment. Enrolled patients included those who completed or withdrew early from the double-blind, randomized, placebo-controlled phase 3 studies GEMINI I and II. The interim reports published today in the Journal of Crohn's & Colitis represent efficacy data collected from May 22, 2009 to June 27, 2013. Outcomes of clinical response, remission and HRQL were assessed for up to 152 weeks of treatment in the efficacy population.

"Given that ulcerative colitis and Crohn's are chronic diseases, it is imperative we evaluate a treatment's efficacy and safety over the long-term to assess its continued benefit for patients," Edward V. Loftus, MD, Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. "These latest findings, reflecting continuous use of vedolizumab for up to three years, are encouraging and provide additional information about the potential benefit for vedolizumab as a long-term treatment option for people with ulcerative colitis and Crohn's disease."

About the Interim Analysis  
GEMINI LTS Ulcerative Colitis Analysis 
A total of 894 patients with UC were enrolled in the GEMINI LTS study and constituted the safety population, and a subset of 845 patients with moderately to severely active UC constituted the efficacy population.

As of June 27, 2013, 63 percent of the efficacy population (n=532/845) were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88 percent (n=120/136) were in remission after 104 weeks of exposure (96 percent [n=70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI I (n=32) before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41 percent and 28 percent, respectively, after 52 weeks, an increase from 19 percent and 6 percent, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior TNF antagonist exposure. Durable benefits on HRQL were also observed.

GEMINI LTS Crohn's Disease Analysis 
A total of 1,349 patients with CD enrolled in the GEMINI LTS study and constituted the safety population. The efficacy population comprised 1,297 patients with moderately to severely active CD: 700 from GEMINI II, 372 from GEMINI III, and 225 vedolizumab-naïve patients.

Among patients with response at week 6 in GEMINI II who received vedolizumab continuously, 83 percent (n=100/120) and 89 percent (n=62/70) of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks (GEMINI II) to every 4 weeks (GEMINI LTS) improved outcomes in patients who had withdrawn early from GEMINI II, with 47 percent (n=27/57) experiencing clinical response and 32 percent (n=18/57) in remission at week 52 of GEMINI LTS (up from 39 percent and 4 percent before the dose increase). Similar improvements were observed regardless of prior TNF antagonist exposure. Long-term benefits of HRQL were also observed.

Patients who were previously exposed to vedolizumab in the GEMINI II and GEMINI III trials demonstrated a reduction in disease activity which was sustained with long-term open-label vedolizumab therapy. After an additional 100 weeks (week 152) of treatment, 74 percent (n=156/212) of all patients who completed GEMINI II were in remission including 66 percent (n=75/113) of those with prior TNF antagonist failure and 82 percent (n=69/84) of TNF antagonist naïve patients. Long-term benefits of HRQL were also observed.

"This latest data from GEMINI LTS provide clinicians and patients valuable information regarding the durability of treatment response to vedolizumab over time," said Michael Smyth, Executive Medical Director, Takeda Pharmaceuticals. "At Takeda, we are committed to continuing this important research to further characterize vedolizumab's benefit: risk profile as a treatment option for patients with moderately to severely active ulcerative colitis and Crohn's disease."

Vedolizumab is a gut-selective humanized monoclonal antibody, approved in over 50 countries. It is the first and only biologic therapy to be approved simultaneously for the treatment of adults with moderately to severely active UC or CD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumor necrosis factor-alpha antagonist.

About Ulcerative Colitis and Crohn's Disease  
Ulcerative colitis (UC) and Crohn's disease (CD) are marked by inflammation in the GI 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 address in 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 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 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.

SOURCE Takeda Pharmaceutical Company Limited

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