Safety and Efficacy of Subcutaneous Entyvio® (Vedolizumab) Sustained During Long-term Maintenance Therapy in Adults with Moderately to Severely Active Ulcerative Colitis

• Interim analysis from VISIBLE OLE study showed long-term findings consistent with the known safety profile of vedolizumab with maintained rates of clinical remission and corticosteroid-free clinical remission
• Entyvio^® was the first maintenance biological therapy approved across Europe in both intravenous (IV) and subcutaneous (SC) formulations to treat moderately to severely active ulcerative colitis or Crohn’s disease
• Latest data presented at the United European Gastroenterology Week (UEG Week) Virtual 2020 congress

OSAKA, Japan--(BUSINESS WIRE)-- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced interim results from the VISIBLE open-label extension (OLE) study on the long-term safety and efficacy of maintenance treatment with the subcutaneous (SC) formulation of the gut-selective biologic Entyvio^® (vedolizumab) in patients with moderately to severely active ulcerative colitis (UC). In evaluating the primary safety endpoint of the trial, interim data of the UC patient population showed that following two years of maintenance therapy with vedolizumab SC, long-term safety findings were consistent with the known safety profile of vedolizumab.¹ Patients also continued to demonstrate clinical benefit from treatment, through maintenance of clinical remission* and corticosteroid-free clinical remission** rates, the clinical efficacy outcomes of the trial.¹ These data were announced in an oral presentation at the UEG Week Virtual 2020 congress.

VISIBLE OLE is an ongoing open-label, phase 3b, multinational, multicenter study to evaluate the long-term safety and tolerability of vedolizumab SC in adult patients with ulcerative colitis or Crohn’s disease (CD), following enrolment and participation in the VISIBLE 1 (UC) or VISIBLE 2 (CD) studies.^1,2 Participants who completed the maintenance period up to week 52 (randomized completers), or who achieved clinical response at week 14 after a third vedolizumab IV infusion at week 6 (non-randomized week 14 responders), received vedolizumab SC 108 mg every two weeks.^1,2 Interim data from the VISIBLE OLE study in the UC patient population demonstrated that adverse events were consistent with the known safety profile of vedolizumab.¹ During two years of maintenance treatment, adverse events occurred in 69% of patients with UC, with disease exacerbations (18%), nasopharyngitis (11%), upper respiratory tract infection (9%), and anemia (7%) reported most frequently.¹ Injection site reactions were reported in 4.5% of patients and all were mild or moderate in severity.¹ Serious adverse events occurred in 14% of patients, with no cases of progressive multifocal leukoencephalopathy and no deaths.¹

In randomized completers, rates of clinical remission and corticosteroid-free clinical remission were maintained up to week 108 (week 6: 71.0% [n=49/69] and week 108: 68.9% [n=42/61], respectively; week 52: 78.3% [n=18/23] to week 108: 70.0% [n=14/20], respectively).¹ In non-randomized week 14 responders, the comparative rates were 62.6% [n=67/107] at week 14 and 33.3% [n=31/93] at week 110 for clinical remission, and 24.5% [n=12/49] at week 54 and 25.0% [n=11/44] at week 110 for corticosteroid-free clinical remission.¹

“These latest safety and effectiveness data for vedolizumab SC provide additional support/data that the benefits received from subcutaneous vedolizumab are sustained during long-term maintenance therapy,” said Asit Parikh, MD PhD, Head of Takeda’s Gastroenterology Therapeutic Area Unit. “Entyvio^® SC was approved by the European Commission in May 2020, offering greater choice on mode of administration in line with the diverse medical needs and preferences of patients, plus the option of home-administration outside of the medical setting. Takeda’s commitment to gastrointestinal innovation continues and we are working to develop a needle-free jet injector application that would broaden choice for patients even further.”

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About the VISIBLE Clinical Trial Program

The VISIBLE clinical trial program aims to assess the efficacy and safety of a subcutaneous (SC) formulation of vedolizumab as maintenance therapy in adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD).

The VISIBLE program consists of three phase 3 studies involving over 1,000 UC and CD patients which includes two randomized, double-blind, placebo-controlled studies examining the proportion of patients achieving clinical remission at week 52, and an open-label extension study to determine the long-term safety and efficacy of vedolizumab SC.^2,3,4

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).⁵ Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract, with CD potentially progressing over time.^6,7 UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.^8,9 CD can also affect the entire thickness of the bowel wall while UC only involves the innermost lining of the large intestine.^8,9 UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus.^8,10 CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.⁶ 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.^8,11,12

About Entyvio^® (vedolizumab)

Vedolizumab is a gut-selective biologic and is approved in both intravenous (IV) and subcutaneous (SC) formulations.^13,14 The SC formulation is currently approved in Europe, Canada and Australia only. 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).¹⁵ MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.¹⁶ The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.¹⁵ These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).^15,17,18 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.¹⁵

Vedolizumab 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.^13,14 Vedolizumab has been granted marketing authorization in over 70 countries, including the United States and European Union, with more than 510,000 patient years of exposure to date.¹⁹

Therapeutic Indications for vedolizumab

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 for vedolizumab

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use

Intravenous 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 intravenous vedolizumab. Observe patients during infusion and until the infusion is complete.

Infusion-related reactions and Hypersensitivity 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. No systemic immunosuppressive effect was noted in healthy subjects. 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, injection site reactions and anaphylaxis.

Injection Site Reactions (subcutaneous vedolizumab)

No clinically relevant differences in the overall safety profile and adverse events were observed in patients who received subcutaneous vedolizumab compared to the safety profile observed in clinical studies with intravenous vedolizumab with the exception of injection site reactions (with subcutaneous administration only). Injection-site reactions were mild or moderate in intensity, and none were reported as serious.

Please consult with your local regulatory agency for approved labeling in your country.

For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO^®.

For U.S. audiences, please see the full Prescribing Information, including Medication Guide for ENTYVIO^® IV.

Takeda in Gastroenterology

We believe that GI and liver diseases are not just life disrupting conditions, but diseases that can impact a patient’s quality of life.^20,21 Beyond a fundamental need for effective treatment options, we understand that improving patients’ lives also depends on their needs being recognized. With nearly 30 years of experience in gastroenterology, Takeda has made significant strides in addressing GI patient needs with treatments for inflammatory bowel disease (IBD), acid-related diseases, short bowel syndrome (SBS), and motility disorders. We are making significant strides toward closing the gap on new areas of unmet needs for patients who have celiac disease, eosinophilic esophagitis, alpha-1 antitrypsin-associated liver disease, Crohn’s disease, and acute pancreatitis, among others. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI.

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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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. For more information, visit https://www.takeda.com.

Important Notice

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Forward-Looking Statements

This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov. Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results.

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References

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² Vedolizumab Subcutaneous Long-Term Open-Label Extension Study. Available at: https://clinicaltrials.gov/ct2/show/NCT02620046 Last updated: March 13, 2020. Last accessed: October 2020.

³ Efficacy and safety of vedolizumab subcutaneously (SC) as maintenance therapy in ulcerative colitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02611830. Last updated: January 23, 2020. Last accessed: October 2020.

⁴ Efficacy and safety of vedolizumab subcutaneous (SC) as maintenance therapy in Crohn’s disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02611817. Last updated: June 23, 2020. Last accessed: October 2020.

⁵ Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.

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

⁹ Feuerstein JD, Cheifetz AS. Crohn’s disease: Epidemiology, diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103.

¹⁰ Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.

¹¹ 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.

¹² 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.

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¹⁴ Entyvio EPAR _ 20/02/2019 Entyvio - EMEA/H/C/002782_ European Medicines Agency - Entyvio _ Annex I Summary of product characteristics. Committee For Medicinal Products For Human Use. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/entyvio. Last updated: May 2020. Last accessed: October 2020.

¹⁵ 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.

¹⁶ 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.

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