FOR MEDICAL MEDIA
Favorable Benefit: Risk Profile for Vedolizumab as Induction and Maintenance Therapy in TNF-Naïve or TNF-Failure Patients with Moderately to Severely Active Ulcerative Colitis Published in Clinical Gastroenterology and Hepatology
Analysis showed consistent treatment benefit irrespective of prior treatment
history with TNF antagonist
Osaka, Japan, September 16, 2016 –Takeda Pharmaceutical Company Limited [TSE: 4502],(“Takeda”) announced that an exploratory analysis of the GEMINI 1 data, evaluating Entyvio (vedolizumab) therapy in patients with ulcerative colitis (UC) based on their treatment history with tumor necrosis factor (TNF) antagonists was published in Clinical Gastroenterology and Hepatology. The sub-group analysis, compared TNF-naïve with TNF-failure patients with moderately to severely active UC. The former had never received TNF antagonist therapy whilst those who had received and failed therapy due to inadequate response, loss of response or intolerance were in the latter group. Overall, the publication reported a statistically significantly greater efficacy with vedolizumab treatment compared to placebo in both sub-groups of patients.
“Approximately 50% of patients with ulcerative colitis do not respond to TNF antagonist therapy, or lose response over time. Healthcare professionals realize that failure of TNF antagonist treatment can be a predictor of poor prognosis and these patients need alternative approaches to achieve sustained remission of symptoms,”1 said Professor Brian Feagan, MD, Robarts Clinical Trials, Robarts Research Institute, at the University of Western Ontario in London, Canada. “These efficacy findings underscore the importance of vedolizumab as a treatment for appropriate patients with moderate to severely active ulcerative colitis, both as first-line biologic therapy in both patients who have never received TNF antagonist treatment or who have failed these agents.”
Investigators examined primary and secondary outcomes data from the GEMINI 1 study, after 6 weeks and 52 weeks of vedolizumab therapy in patient sub-groups who were either TNF-naïve or failed TNF antagonist therapy. The analysis reported that vedolizumab treatment had statistically significantly greater efficacy compared to placebo in inducing and maintaining clinical response in both sub-groups of patients. Furthermore, greater treatment differences favoring vedolizumab treatment at week 6 were observed for TNF-naïve patients, compared to TNF-failure patients. There were no differences in adverse events among treatment groups in this study.1
“Ulcerative colitis requires life-long management, and symptoms can cause patients a significant impact on their daily lives, if they are not adequately controlled. As the global burden of inflammatory bowel disease is so high, Takeda is committed to continuing our research and development efforts to help these patients,” explained Asit Parikh, MD, PhD, senior vice president, Head Gastroenterology Therapeutic Area, Takeda. “These data indicate that vedolizumab is an effective therapeutic option for ulcerative colitis and it potentially has a better effect in biologic-naïve patients, compared to those who have previously failed a TNF antagonist.”
About the Analysis
Investigators evaluated predefined outcomes data from the GEMINI 1 clinical trial (Phase 3) of vedolizumab examining treatment with vedolizumab in patients with moderately to severely active UC.1
GEMINI 1 was a multicenter, phase 3, randomized, placebo-controlled trial (additional study details further below). As part of the eligibility criteria for GEMINI 1, patients had demonstrated, within the previous 5-year period, an inadequate response to, loss of response to, or intolerance of ≥1 of the following therapies: corticosteroids (outside the United States only), immunosuppressives (azathioprine or mercaptopurine), and/or infliximab, as this was the only TNF antagonist approved for the treatment of UC at the time of enrollment.
GEMINI 1 enrolled 464 patients without prior TNF antagonist therapy (TNF-naïve) and 367 who had failed therapy because of inadequate response, loss of response or intolerance (TNF-failure).1 In the present analyses, the TNF-failure population comprised an aggregate of patients with inadequate response, loss of response, or intolerance to prior TNF antagonist treatment as pre-defined according to data captured on the case report form (CRF) at baseline (week 0).1
The primary outcome measure for induction therapy was a clinical response at week 6. Secondary outcome measures were clinical remission and mucosal healing at week 6. For maintenance therapy, the primary outcome was clinical remission at week 52.1
Efficacy outcomes in TNF-naïve and TNF-failure patient sub-groups were analyzed in terms of the absolute difference in percentages for vedolizumab and placebo and the risk ratios (RRs). The RR is a measure of treatment efficacy, adjusted for any variabilities within the patient sub-groups, with RR > 1 indicating greater efficacy with vedolizumab.1
Investigators found greater absolute differences between vedolizumab and placebo for TNF-naïve patients than for TNF-failure patients at week 6 and the RRs were similar. Week 6 response rates with vedolizumab and placebo were 53.1% and 26.3%, respectively, in TNF-naïve patients (AD: 26.4%; 95% confidence interval [CI]: 12.4, 40.4; RR: 2.0; 95% CI: 1.3, 3.0) and 39.0% and 20.6%, respectively, in TNF-failure patients (AD: 18.1%; 95% CI: 2.8, 33.5; RR: 1.9; 95% CI: 1.1, 3.2).1
During maintenance, the absolute differences were similar and the RRs were higher for TNF-failure patients for most outcomes. Week 52 remission rates with vedolizumab and placebo were 46.9% and 19.0%, respectively, in TNF-naïve patients (AD: 28.0%; 95% CI: 14.9, 41.1; RR: 2.5; 95% CI: 1.5, 4.0) and 36.1% and 5.3%, respectively, in TNF-failure patients (AD: 29.5%; 95% CI: 12.8, 46.1; RR: 6.6; 95% CI: 1.7, 26.5).1
Vedolizumab was approved as a gut-selective humanized monoclonal antibody, available in the European Union under the trade name Entyvio (vedolizumab). Entyvio was also approved in the United States in 2014. Entyvio is now approved in 48 countries, across five continents. 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.3,4
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.6 These cells have been shown to play a role in mediating the inflammatory process in UC and CD. 6, By inhibiting alpha4beta7, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.6
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.
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
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.
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.
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.
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.
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.
Danny Stepto For Japanese media
TEL: +41-44-555-1504 Kazumi Kobayashi [email protected] TEL: +81-3-3278-2095
# # #
 Feagan, Rubin, Danese, et al. Vedolizumab induction and maintenance in ulcerative colitis patients by prior tumor necrosis factor antagonist exposure. Clinical Gastroenterology and Hepatology. 2016
 Entyvio Summary of Product Characteristics. May 2014.
 National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Digestive Diseases Information Clearinghouse. Ulcerative colitis. http://digestive.niddk.nih.gov/ddiseases/pubs/colitis/index.aspx. Published September 2014. Accessed January 14, 2015.
 National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Digestive Diseases Information Clearinghouse. Crohn’s disease. http://digestive.niddk.nih.gov/ddiseases/pubs/crohns/index.aspx. Published September 2014. Accessed January 14, 2015.
 Crohn’s and Colitis Foundation of America. The facts about inflammatory bowel disease. http://www.ccfa.org/assets/pdfs/ibdfactbook.pdf. Published June, 2011. Accessed January 4, 2013.
 Soler D, Chapman T, Yang L, Wyant T, Egan R, Fedyk E. 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(3):864-875. http://jpet.aspetjournals.org/content/330/3/864.full.pdf+html. Published June 9, 2009. Accessed December 6, 2013.
 Briskin M, Winsor-Hines D, Syjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. American Journal of Pathology. 1997;51(1):97.
 Gledhill T, Bodger K. New and emerging treatments for ulcerative colitis: a focus on vedolizumab. Biologics: targets and therapy. 2013;7:123-130.