GEMINI II & III Post-hoc Analysis Reports Clinical Benefits of Vedolizumab as Induction and Maintenance Therapy in Tumor Necrosis Factor-Naive Patients with Moderately to Severely Active Crohn's Disease

Analysis published in Inflammatory Bowel Diseases showed vedolizumab provides additional treatment option for both tumor necrosis factor-naive and tumor necrosis factor-failure patients

Osaka, Japan, December 9, 2016 - Takeda Pharmaceutical Company Limited [TSE: 4502], （“Takeda”） announced that an analysis based on pre-specified and post-hoc exploratory outcomes of GEMINI II and GEMINI III data evaluating Entyvio （vedolizumab） therapy in patients with moderately to severely active Crohn’s disease （CD） was published in Inflammatory Bowel Diseases. The data demonstrated higher rates of response in patients receiving vedolizumab as a first-line biologic after conventional therapy failure versus patients who had previously experienced tumor necrosis factor-alpha （TNF-α） antagonist therapy failure. ¹

Among patients who responded to vedolizumab induction at week 6, 48.9 percent of TNF-naive and 27.7 percent of TNF-failure patients were in remission with vedolizumab at week 52 （vs 26.8 percent and 12.8 percent with placebo）. ¹

“Treatment failure with TNF-α antagonists is associated with a lower clinical response to any subsequent tumor necrosis factor antagonist, so physicians and patients should consider alternative approaches to achieve sustained remission of symptoms,” said Bruce E. Sands, MD, MS, Chief of the Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai in New York. ² “This analysis further supports the value of vedolizumab, not only as a treatment alternative in patients who have failed TNF-α antagonistic therapy, but also as first-line treatment after conventional therapy failure.”

Investigators examined data from 516 patients who were TNF-naive and 960 patients who had failed prior TNFα antagonist therapy in the combined GEMINI II and GEMINI III study populations. ¹

In TNF-naive patients who achieved remission, the treatment difference from placebo was significant at week six （12.6 percent difference; 95 percent CI: 3.7, 21.4） and week 10 （11.3 percent difference; 95 percent CI: 1.5, 21.1）. For TNF-failure patients who achieved remission, the treatment difference from placebo reached significance at week 10 （11.5 percent difference; 95 percent CI: 4.5, 18.6）. ¹ There were no differences in adverse events among treatment groups in this study. ¹

In this analysis, compared to placebo, treatment with vedolizumab also showed clinical efficacy of vedolizumab maintenance therapy at week 52 irrespective of the number of prior TNF-α antagonist failed. Additionally, trends favoring vedolizumab induction were observed across all three measures of TNF-α antagonist failure assessed in the study: inadequate response, loss of response or intolerance, and number of prior TNF-α antagonists used. As clinical response/remission rates may be diminished when switching to a second or third TNF-α antagonist, these results support evaluating a treatment switch; to a therapy with a different mode of action, such as vedolizumab. ^{1, 3, 4, 5, 6}

“Crohn’s disease is a chronic inflammatory condition resulting in significant impairment of quality of life and requires long-term management with an effective, safe therapy. The primary goal of therapy is to
induce and maintain clinical remission as effectively as possible,” stated Sharon O’Byrne, MD, Vice President, Global Medical Head, Specialty GI, Takeda Pharmaceuticals.

About GEMINI II and GEMINI III
Results from GEMINI II, a placebo-controlled induction and maintenance study in patients with moderately to severely active CD, showed that vedolizumab demonstrated statistically significant improvement in the primary endpoint of clinical remission （CDAI score ≤150 points） at six weeks and at 52 weeks compared to placebo. At six weeks, no significant difference was observed in the other primary endpoint of CDAI-100 response （≥100-point decrease in the CDAI score） between the vedolizumab and placebo groups. A significantly greater proportion of patients showed CDAI-100 response and corticosteroid-free remission at 52 weeks. The most common adverse events reported in the 814 patient vedolizumab arm （＞8.0 percent） were CD exacerbation, arthralgia, pyrexia, nasopharyngitis, headache, nausea and abdominal pain. The most common adverse events reported in the 301 patient placebo arm were （≥8.0 percent） CD exacerbation, headache, arthralgia, pyrexia, abdominal pain, nausea and nasopharyngitis. ⁷

In GEMINI III, the clinical remission rate at six weeks was not statistically significant between vedolizumab and placebo groups in moderately to severely active CD patients who had previously failed therapy with TNFα antagonists. ⁸However, significantly greater proportions of vedolizumab-treated patients had CDAI-100 response （≥100-point CDAI score decrease from baseline） at week 6 and were in clinical remission by week 10 in the anti-TNF failure and in the overall populations compared with placebo. At week 10, a higher proportion of this population given vedolizumab was in remission （26.6 percent） than those given placebo （12.1 percent）.

The clinical remission rate at six weeks for the patients who had failed TNFα antagonists was 15.2 percent （24/158） for the vedolizumab treated patients versus 12.1 percent （19/157） for those who received placebo. The primary and secondary outcome results suggest that in patients with CD and previous TNF antagonist failure, effects of vedolizumab on clinical remission may not become evident until between weeks 6 and 10. The most common adverse events （≥4 percent） reported in the vedolizumab arm were: nausea, headache, arthralgia, nasopharyngitis, abdominal pain, upper respiratory tract infection and vomiting. ^{8, 9}

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 54 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 ulcerative colitis （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. ⁹

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. ¹⁰CD can impact any part of the digestive tract and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and fever. ¹¹ 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. ¹² 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. ^{10, 11}

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）. ¹³ MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. ¹⁴The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. ¹³These cells have been shown to play a role in mediating the inflammatory process in UC and CD. ^13,15 By inhibiting alpha4beta7, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues. ¹³

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.

Contacts:

Danny Stepto
TEL:+41-44-555-1504
[email protected]

For Japan Media:
Tsuyoshi Tada
TEL:+81-33-278-2417
[email protected]

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