OSAKA, Japan, and CAMBRIDGE, Massachusetts, February 3, 2022 – Takeda (TSE:4502/NYSE:TAK) today announced that the European Commission has granted marketing authorization for the intravenous (IV) formulation of vedolizumab 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. Vedolizumab is the first treatment indicated for active chronic pouchitis across the European Union.
The European Commission approval was based on the EARNEST trial, recently presented at the United European Gastroenterology’s annual meeting, UEG Week Virtual 2021. Further data from the study is set to be shared at the European Crohn’s and Colitis Organisation’s annual congress 2022 on the 17 February 2022.1 The EARNEST trial assessed the safety and efficacy of vedolizumab IV in the treatment of active chronic pouchitis.2,3 Furthermore, information from a number of retrospective studies indicating that vedolizumab can have a positive impact on patients with inflammation of the pouch was also included in the application.4,5,6
IPAA, also known as J-pouch surgery, is a procedure used to help patients who have had their colon and rectum removed (proctocolectomy) pass stools normally. Pouchitis is a complication after proctocolectomy with IPAA in UC patients which can have a significant impact on quality of life.7,8 Pouchitis is the most common complication of an IPAA, with a reported incidence rate between 23% and 59% in patients with UC.9 Chronic pouchitis, which affects 10-15% of patients with pouchitis globally,8,10,11 does not adequately respond to antibiotic therapy.12
“We are pleased that the European Commission has approved intravenous vedolizumab for the treatment of active chronic pouchitis,” said Wolfram Nothaft, Chief Medical Officer, Takeda. “Chronic pouchitis is a disease area with huge unmet need and we are proud to be able to provide a valuable treatment option which supports people living with this condition.”
Following the news of the European Commission approval, Takeda is now pursuing local reimbursement to enable access to this first treatment for active chronic pouchitis in Europe as soon as possible as part of its continued commitment to patients with gastrointestinal diseases.
Patients with ulcerative colitis (UC) may require removal of their colon and rectum (proctocolectomy), and the surgical creation of an ileal pouch to aid stool retention (ileal pouch-anal anastomosis or IPAA). Pouchitis is the most common complication of an IPAA, with a reported incidence rate between 23% and 59% in patients with UC.9 Acute pouchitis may respond to antibiotic therapy, however until now there were no approved therapies indicated for active chronic pouchitis in the European Union, which does not respond to antibiotic therapy, and where patients frequently relapse.12,13,14 Chronic 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. 8,10,11,15
EARNEST is a randomized, double-blind, placebo-controlled multicenter study that evaluated the efficacy and safety of vedolizumab IV in the treatment of 102 adult patients with UC who had undergone a proctocolectomy and IPAA, and had developed active chronic pouchitis, defined as patients who had inadequate response with or lost response to antibiotics therapy. The EARNEST study met its primary endpoint of clinical remission at week 14. Measured using the modified Pouchitis Disease Activity Index (mPDAI), clinical remission rates were 31.4% (95% CI: 19.1% – 45.9%) in patients in the vedolizumab IV arm (n=51), compared with 9.8% (95% CI: 3.3% – 21.4%) in the placebo arm (n=51) (p=0.013). Safety findings were in line with general use of vedolizumab. Adverse events (AEs) were reported in 47 (92.2%) and 44 (86.3%) of patients treated with vedolizumab and placebo, respectively. Treatment-related AEs (as assessed by the investigator) were reported in 12 (23.5%) and 11 (21.6%) of patients treated with vedolizumab and placebo, respectively. Serious AEs were reported in 3 (5.9%) and 4 (7.8%) patients treated with vedolizumab and placebo, respectively.2
The EARNEST study was presented at the annual meeting of the United European Gastroenterology, UEG Week Virtual 2021.3 Further data from the study is set to be shared at the European Crohn’s and Colitis Organisation’s annual congress 2022.
Ulcerative colitis (UC) and Crohn’s disease (CD) are two of the most common forms of inflammatory bowel disease (IBD).16 Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract, with CD potentially progressing over time.17,18 UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.19,20 CD can also affect the entire thickness of the bowel wall while UC only involves the innermost lining of the large intestine.19,20 UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus.19,21 CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.17 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.19,22,23
Vedolizumab is a gut-selective biologic and is approved in both intravenous (IV) and subcutaneous (SC) formulations.24,25 The SC formulation is currently approved in Europe, Canada, Australia, and Switzerland 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).26 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.27 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.26 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).26,28,29 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.26
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.24,25 Vedolizumab has been granted marketing authorization in over 70 countries, including the United States and European Union, with more than 740,000 patient years of exposure to date.30
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.
Active chronic pouchitis
Vedolizumab is indicated 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.
Hypersensitivity to the active substance or to any of the excipients.
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.
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 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.
The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease. Immunomodulatory medicinal products may increase the risk of malignancy.
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.
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.
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.
We believe that GI (gastrointestinal) and liver diseases are not just life-disrupting conditions, but diseases that can impact a patient’s quality of life.31,32 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 in new areas of unmet need for patients who have celiac disease, eosinophilic esophagitis, alpha-1 antitrypsin-associated liver disease and Crohn’s disease, among others. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI.
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). 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.
+81 (0) 3-3278-3414
U.S. and International Media
For the purposes of this notice, “release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws. The companies in which Takeda directly and indirectly owns investments are separate entities. In this release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.
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, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; 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/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.
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.
1 Travis S, Silverberg MS, Danese S, et al. OP04 Vedolizumab intravenous is effective across multiple treatment targets in chronic pouchitis: Results of the randomised, double-blind, placebo-controlled EARNEST trial. J Crohns Colitis. 2022;16(Supplement_1):i004–5.
2 Phase 4 Study to Evaluate the Efficacy and Safety of Vedolizumab in the Treatment of Chronic Pouchitis (EARNEST). Available at: https://clinicaltrials.gov/ct2/show/NCT02790138. Last updated: 30 June 2021. Last accessed: February 2022.
3 Travis S, Osterman M, Danese S, Gionchetti P, Lowenberg M, Lindner D, et al. P0448 Efficacy and Safety of Intravenous Vedolizumab for Treatment of Chronic pouchitis: Results of The Phase 4 EARNEST Trial. United European Gastroenterol J. 2021 Oct;9(9_suppl):531.
4 Hirsch A, Tulchinsky H, Maharshak N. P693 Vedolizumab treatment for pouch inflammation. J Crohns Colitis. 2019;13(supplement 1):S467.
5 Ribaldone DG, Pellicano R, Saracco GM, et al. Vedolizumab for treatment of chronic refractory pouchitis: a systematic review with pool analysis. Rev Esp Enferm Dig. 2020;112(1):59–63.
6 Gregory MH, Hicks SB, Hoversten P, et al. Mo1900 - Vedolizumab for the treatment of pouchitis. Gastroenterology. 2018;154(6):S844-S845.
7 Nishida Y, Hosomi S, Yamagami H, et al. Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio. PLOS ONE https://doi.org/10.1371/journal.pone.0241322 October 26, 2020.
8 Singh A, Khan F, Lopez R, et al. Vedolizumab for chronic antibiotic refractory pouchitis. Gastroenterology. 2019;7(2):121-126.
9 Chandan S, Mohan BP, Kumar A, et al. Safety and Efficacy of Biological Therapy in Chronic Antibiotic Refractory Pouchitis: A Systematic Review With Meta-analysis. J Clin Gastroenterol. 2021;55:481-491.
10 Verstockt B, Claeys C, Van Assche G, et al. P624 Vedolizumab can induce clinical remission in patients with chronic antibiotic-refractory pouchitis: A retrospective single-centre experience. J Crohns Colitis. 2018;12(supplement 1):S425.
11 Bar F, Kuhbacher T, Dietrich NA, et al. Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis. Aliment Pharmacol Ther. 2017;47(5):581-587.
12 Dalal RL, Shen B, Schwartz DA. Management of Pouchitis and Other Common Complications of the Pouch. Inflamm Bowel Dis. Volume 24, Number 5, May 2018.
13 Akiyama S, Rai V, Rubin DT. Pouchitis in inflammatory bowel disease: a review of diagnosis, prognosis, and treatment. Intestinal Research. 2021;19(1):1-11.
14 Shen B, Achkar JP, Lashner BA, et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis. 2001;7(4):301–5.
15 Schieffer KM, Williams ED, Yochum GS, et al. Review article: the pathogenesis of pouchitis. Aliment PharmacolTher 2016; 44: 817–835.
16 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.
17 Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605.
18 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363.
19 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.
20 Feuerstein JD, Cheifetz AS. Crohn’s disease: Epidemiology, diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103.
21 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.
22 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.
23 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.
24 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. Last updated: March 2020. Last accessed: February 2022.
25 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: February 2022.
26 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.
27 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.
28 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312.
29 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.
30 Takeda data on file (VV-SUP-91507): Vedolizumab Patient Exposure from Marketing Experience. 2021.
31 Center for Drug Evaluation and Research (CDER) & the FDA. The Voice of the patient/functional gastrointestinal disorder. 2016. Available at: https://www.fda.gov/media/95140/download. Last accessed: February 2022
32 Jones R, Hunt C, Stevens R, et al. Management of common gastrointestinal disorders: quality criteria based on patients’ views and practice guidelines. Br J Gen Pract. 2009;59:e199-208.