New Exploratory Data from VARSITY, First Head-to-Head Ulcerative Colitis Biologic Study Which Demonstrated Superiority of Vedolizumab to Adalimumab in Clinical Remission at Week 52, Presented at 2019 Digestive Disease Week®

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced further results from the Phase 3b head-to-head VARSITY study, which demonstrated that the gut-selective biologic vedolizumab (Entyvio^®) was superior to the anti-tumor necrosis factor-alpha (anti-TNFα) biologic adalimumab (Humira^®) in achieving clinical remission* at week 52 in patients with moderately to severely active ulcerative colitis (UC).¹ New exploratory data showed that a greater proportion of patients receiving vedolizumab intravenous (IV) achieved clinical response** at week 14 compared to those treated with adalimumab subcutaneous (SC), 67.1% vs. 45.9% respectively. A separation between the treatment groups was seen as early as week 6, favoring vedolizumab. These results were announced in a Distinguished Abstract Plenary Lecture Presentation at the 2019 Digestive Disease Week^® (DDW) annual scientific meeting (May 18-21 in San Diego, CA), one of 18 Takeda sponsored vedolizumab abstracts accepted for presentation.²

Additional exploratory data on absence of active histologic disease were also presented at the meeting. Histologic disease activity is an endpoint assessing the degree of microscopic inflammation in the gut. Absence of active histologic disease is achieved when inflammation is less than a pre-defined severity threshold.^2,3,4*** In the VARSITY study, consistent results were seen with vedolizumab treatment across both the Geboes Score (<3.2) and Robarts Histopathology Index (<5), with absence of active histologic disease achieved in 33.4% and 42.3% of patients treated with vedolizumab, respectively, compared with 13.7% and 25.6% of patients treated with adalimumab, respectively.²

“Exploratory data from the VARSITY study suggest that more patients experienced early symptomatic response and improvement of microscopic intestinal inflammation with vedolizumab as compared to adalimumab,” said Dr. Bruce E. Sands, primary investigator of the VARSITY study and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai in New York. “In clinical practice there is a need to balance early symptomatic improvement alongside the longer-term treatment goal of helping patients to achieve clinical remission, making these findings important to physicians.”

“Patients benefit from clinical trials that advance our understanding of the disease. The VARSITY study, a first-of-its-kind comparison of two biologics in ulcerative colitis, provides valuable information that can help inform treatment decisions, while also increasing our understanding of how these treatments are working at a microscopic level,” said Jeff Bornstein, M.D., Executive Medical Director, Takeda. “Data from the VARSITY study show consistent results for vedolizumab, supporting the use of this treatment as a first-line biologic therapy in ulcerative colitis.”

About VARSITY
VARSITY is a Phase 3b, randomized, double-blind, double-dummy, multi-center, active-controlled study to evaluate the efficacy and safety of vedolizumab intravenous (IV) compared to adalimumab subcutaneous (SC) at week 52 in patients with moderately to severely active ulcerative colitis. The study randomized 769 patients (vedolizumab n=383 or adalimumab n=386), all of whom had inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or one tumor necrosis factor-alpha (TNFα)-antagonist other than adalimumab prior to being enrolled. Patients were randomized into one of two treatment groups, vedolizumab IV 300 mg and placebo SC or adalimumab SC 160 mg and placebo IV. Dose escalation was not permitted in either treatment arm during the study.^1,5

At week 52, 31.3% (n=120/383) of patients receiving vedolizumab IV achieved the primary endpoint of clinical remission* compared to 22.5% (n=87/386) of patients treated with adalimumab SC, with the difference being statistically significant (p=0.0061). In addition, 39.7% of patients treated with vedolizumab achieved the secondary endpoint of mucosal healing^± at week 52, compared to 27.7% receiving adalimumab (p=0.0005). A non-statistically significant difference in favor of adalimumab was seen in the percentage of patients using oral corticosteroids at baseline who discontinued corticosteroids and were in clinical remission^† at week 52. While the study was not powered to compare the safety of the two biologics, patients treated with vedolizumab (62.7%) had a lower rate of overall adverse events than patients treated with adalimumab (69.2%), with a lower rate of infections reported in patients treated with vedolizumab (33.5%) as compared to adalimumab (43.5%). The rate of serious adverse events was also lower in vedolizumab-treated patients than adalimumab (11.0% vs. 13.7% respectively).¹

* Primary endpoint: Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore ˃1 point.5

** Exploratory endpoint: Clinical response is defined as a reduction in partial Mayo score of ≥2 points and ≥25% from baseline, with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. Patients with missing clinical response status were considered non-responders.2

*** Exploratory endpoint: Absence of active histologic disease is defined as a Geboes Score (<3.2) or Robarts Histopathology Index (<5).2

± Secondary endpoint: Mucosal healing is defined as Mayo endoscopic subscore of ≤1 point. Mayo score: instrument designed to measure disease activity of ulcerative colitis.5

† Secondary endpoint: Corticosteroid-free clinical remission is defined as patients using oral corticosteroids at baseline (week 0) who have discontinued oral corticosteroids and are in clinical remission at week 52.5

About Digestive Disease Week ^® (DDW)
Digestive Disease Week^® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 18-21, 2019, at the San Diego Convention Center. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at www.ddw.org.

About Ulcerative Colitis
Ulcerative colitis (UC) is one of the most common forms of inflammatory bowel disease (IBD).⁶ UC is a chronic, relapsing, remitting, inflammatory condition of the gastrointestinal tract that is often progressive in nature, and involves the innermost lining of the large intestine.^7,8 UC commonly presents with symptoms of abdominal discomfort and loose bowel movements, including blood or pus.^8,9 The cause of UC 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 the condition.^8,10,11

About Entyvio ^® (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.¹² It is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), 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.¹⁴ The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.¹³ These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).^13,15,16 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.¹³

Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active UC and CD, 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.¹² Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 260,000 patient years of exposure to date.¹⁷

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 specific to 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. 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. 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, fatigue and anaphylaxis.

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/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.

For more information, visit https://www.takeda.com

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References

1 Schreiber S, Peyrin-Biroulet L, Loftus EV Jr, et al. VARSITY: A double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. J CrohnsColitis. 2019;13(Supplement_1):S612–3.

2 Sands B, Peyrin-Biroulet, L, Loftus EV Jr, et al. Vedolizumab shows superior efficacy versus adalimumab: Results of VARSITY: The first head-to-head study of biologic therapy for moderate-to-severe ulcerative colitis. Presented at Digestive Disease Week (DDW) San Diego, California. Abstract #416a. (Oral presentation - Sunday, May 19, 2019, 17:16- 17:30 PDT).

3 Peyrin–Biroulet L, Bressenot A, Kampmank W, et al. Histologic remission: The ultimate therapeutic goal in ulcerative colitis? Clin Gastroenterol Hepatol. 2014;12:929–934.

4 Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol. 2012 Nov;107(11):1684-92.

5 An efficacy and safety study of vedolizumab intravenous (IV) compared to adalimumab subcutaneous (SC) in participants with ulcerative colitis. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02497469. Last updated: April 12, 2019. Last Accessed: April 2019.

6 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.

7 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363.

8 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.

9 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.

10 Henckaerts L, Pierik M, Joossens M, et al. Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut. 2007;56:1536-1542.

11 Kaser A, Zeissig S, Blumberg RS. Genes and environment: How will our concepts on the pathophysiology of IBD develop in the future? Dig Dis. 2010;28:395-405.

12 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. Last updated: February 2018. Last accessed: April 2019.

13 Soler D, Chapman T, Yang LL, et al. 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;330:864-875.

14 Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151:97-110.

15 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298-1312.

16 Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis. 2016;10:1437-1444.

17 Takeda Data on File. 2019.

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