Severe infection

−The Phase 4 EARNEST Study Met Its Primary Efficacy Endpoint of Remission of Chronic or Recurrent Pouchitis at Week 14, with 31% of Participants Receiving Vedolizumab Achieving Remission versus 10% Receiving Placebo.1 −Superiority over Placebo Was Also Demonstrated at Week 34, with 35% of Vedolizumab Patients Achieving Remission Compared with 18% on Placebo.1 OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today confirmed that the New England Journal of Medicine (NEJM) has published positive data from the Phase 4 EARNEST study of vedolizumab for the treatment of chronic pouchitis. The NEJM article is titled “Vedolizumab for the Treatment of Chronic Pouchitis”. A potentially curative surgical option for ulcerative colitis (UC) is total proctocolectomy, followed by creation of an ileal pouch anal anastomosis (IPAA) to aid in stool retention. Inflammation of the ileal pouch, pouchitis, can cause fecal incontinence, abdominal discomfort, and bleeding.2 Chronic pouchitis, defined by symptom duration greater than four weeks, can develop in up to one-fifth of these patients.3 The published results showed the Phase 4 EARNEST study met its primary efficacy endpoint of clinical and endoscopic remission, as measured by modified pouchitis disease activity index (mPDAI), at Week 14 in 31% of participants (16 out of 51) receiving vedolizumab versus 10% (5 out of 51) receiving placebo (95% CI: 5 to 38 percentage point [p.p.] difference; p=0.01). This improved outcome compared with placebo was also seen at the equivalent secondary endpoint at Week 34 (35% of vedolizumab patients [18 out of 51] achieved mPDAI remission compared with 18% [9 out of 51] on placebo [95% CI: 0 to 35 p.p. difference]).1 “Pouchitis is relatively common following pouch surgery for people with ulcerative colitis,” said Professor Simon Travis, Translational Gastroenterology Unit and Kennedy Institute, University of Oxford. “Demonstrating the efficacy of a biologic treatment for this inflammatory condition is important for a group of patients who have previously had no treatment option once antibiotics are no longer effective.” Beyond mPDAI remission, patients receiving vedolizumab also demonstrated improved clinical response at both Week 14 and Week 34 over placebo, with a difference at Week 14 of 30 p.p. (95% CI, 8 to 48), and a Week 34 difference of 22 p.p. (95% CI, 2 to 40). Serious adverse events occurred in 6% (3 out of 51) and 8% (4 out of 51) of patients in the vedolizumab and placebo groups, respectively.1 No new safety signals were identified. The publication concluded that vedolizumab was more effective than placebo for inducing remission in chronic pouchitis after IPAA for patients with UC. “We are committed to advancing treatment and care for patients living with debilitating inflammatory gastrointestinal conditions such as active chronic pouchitis,” said Marcelo Freire, Vice President, Global Medical Affairs, Therapeutic Area Head, Gastroenterology, Takeda. “The publication of the latest results from the EARNEST study in the New England Journal of Medicine is great recognition of the work we are doing to reduce the burden of this condition for patients.” Vedolizumab is indicated only in the European Union for the treatment of adult patients with moderately to severely active chronic pouchitis, who have undergone proctocolectomy and IPAA for UC and have had an inadequate response with or lost response to antibiotic therapy.4 In the United States, vedolizumab is indicated in adults for the treatment of moderately to severely active UC and Crohn’s disease (CD).5 About Pouchitis Patients with ulcerative colitis (UC) may require removal of their colon and rectum (proctocolectomy), and the surgical creation of an ileal pouch (ileal pouch-anal anastomosis or IPAA) to aid stool retention. Pouchitis, where inflammation and irritation are seen in the lining of the new pouch, is the most common complication of an IPAA, affecting approximately 50% of patients with UC or familial adenomatous polyposis (FAP).3 Acute pouchitis may respond to antibiotic therapy, however there are currently no approved therapies indicated for active chronic pouchitis in the European Union, including the refractory form of pouchitis, which does not respond to antibiotic therapy, and where patients frequently relapse.3 Refractory pouchitis affects 10-15% of patients with pouchitis, and can have a considerable impact on their quality of life, causing fecal urgency, incontinence, straining during defecation, bleeding, abdominal or pelvic discomfort, fever and malaise.2,6,7 The prevalence of all pouchitis has been calculated to be 12 to 18 patients per 100,000 in the United States.8 About the EARNEST clinical trial EARNEST is a randomized, double-blind, placebo-controlled multicenter study that evaluated the efficacy and safety of vedolizumab IV in the treatment of adult patients with UC who had undergone a proctocolectomy and IPAA, had developed active chronic pouchitis, and had inadequate response with or lost response to antibiotics therapy.9 About Vedolizumab Vedolizumab is a gut-selective biologic and is approved for intravenous (IV) use in the United States and approved in both IV and subcutaneous (SC) formulations in Europe, Canada, Australia, Switzerland and Japan.4,5,10,11,12,13 It is a humanized monoclonal antibody designed to specifically antagonize the α4β7 integrin, inhibiting the binding of α4β7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1).14 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.15 The α4β7 integrin is expressed on a subset of circulating white blood cells.14 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).14,16,17 By inhibiting α4β7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.14 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.4,5 Vedolizumab has been granted marketing authorization in over 70 countries, including the United States and European Union, with more than 1,000,000 patient years of exposure to date.18 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. Pouchitis Vedolizumab IV is indicated in the EU for the treatment of adult patients with moderately to severely active chronic pouchitis, who have undergone proctocolectomy and ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) and have had an inadequate response with or lost response to antibiotic therapy. Important Safety Information for vedolizumab Contraindications Hypersensitivity (such as dyspnea, bronchospasm, urticaria, flushing and increased heart rate) 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. Injection Site Reactions (subcutaneous vedolizumab) No clinically relevant differences in the overall safety pro adverse events were observed in patients who received subcutaneous vedolizumab compared to the safety pro 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. 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. 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. About Takeda Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI), with expertise in immune and inflammatory 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 . 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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. Medical information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. References Travis S, Silverberg MS, Danese S, et al. Vedolizumab for the Treatment of Chronic Pouchitis. N Engl J Med. 2023; 388:1191-1200 Schieffer KM, Williams ED, Yochum GS, et al. Review article: the pathogenesis of pouchitis. Aliment Pharmacol Ther. 2016;44:817–835. Dalal RL, Shen B, Schwartz DA. Management of Pouchitis and Other Common Complications of the Pouch. Inflamm Bowel Dis. 2018;24:989-996. Entyvio Summary of Product Characteristics. Available at: . Last updated: October 2022. Last accessed: February 2023. Entyvio Prescribing Information. Available at: . Last updated: June 2022. Last accessed: March 2023. Singh A, Khan F, Lopez R, et al. Vedolizumab for chronic antibiotic-refractory pouchitis. Gastroenterol Rep (Oxf). 2019;7:121-126. Bär F, Kühbacher T, Dietrich NA, et al. Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis. Aliment Pharmacol Ther. 2018;47:581-587. Sandborn WJ, Pardi DS. Clinical management of pouchitis. Gastroenterology. 2004;127(6):1809–1814. A Study to Evaluate the Efficacy and Safety of Vedolizumab in the Treatment of Chronic Pouchitis (EARNEST). Available at: . Last updated: February 2022. Last accessed: March 2023. Product Monograph including Patient Medication Information. Available at: Last accessed: March 2023 Australian Product Information. Entyvio (vedolizumab). Available at: . Last accessed: March 2023 Fachinformation Entyvio. Swissmedic. October 2020. Takeda Receives Approval to Manufacture and Market Entyvio Subcutaneous Injection in Japan for the Maintenance Treatment of Moderate to Severe Ulcerative Colitis. Available at: Last accessed: March 2023 Soler D, Chapman T, Yang LL, et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-875. 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. Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its role in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312. 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. Takeda data on file (VV-SUP-116025): Vedolizumab Patient Exposure from Marketing Experience. July 2022.