Takeda Presents Constructive Outcomes from Section 3 Examine of Vedolizumab for Prevention of Intestinal Acute Graft-Versus-Host Illness (aGvHD) in Sufferers Present process Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

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OSAKA, Japan & CAMBRIDGE, Mass. — Takeda ( TSE:4502/NYSE:TAK) right this moment introduced late-breaking knowledge from the Section 3 GRAPHITE research introduced on the 2023 Tandem Conferences, demonstrating vedolizumab achieved a statistically vital and clinically significant enchancment in decrease gastrointestinal (GI) aGvHD-free survival by Day 180 after allo-HSCT with no related variations in security profile versus placebo.¹ Intestinal aGvHD is a severe complication characterised by irritation of the GI tract which may have an effect on sufferers present process allo-HSCT, a typical therapy for blood cancers.

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“Decrease GI aGvHD represents a crucial unmet want in sufferers present process allo-HSCT,” mentioned Yi-Bin Chen, MD, Director, Hematopoietic Cell Transplant & Cell Remedy Program, Mass Common Most cancers Heart. “I’m excited that this research can contribute to the understanding of this widespread and life-threatening complication in stem cell transplantation.”

Vedolizumab will not be at present indicated to be used in aGvHD.

The Section 3, randomized, double-blind, placebo-controlled, multicenter GRAPHITE research evaluated the efficacy and security of vedolizumab as prophylaxis for intestinal aGvHD in sufferers present process allo-HSCT from unrelated donors for the therapy of hematological malignancies. The research met its major endpoint, with vedolizumab reaching a statistically vital enchancment in intestinal aGvHD-free survival versus placebo by Day 180 after allo-HSCT (85.5% of sufferers within the vedolizumab arm versus 70.9% within the placebo arm [HR=0.45; 95% CI: 0.27, 0.73; p<0.001]).¹ Statistically vital superiority of vedolizumab over placebo was additionally demonstrated for intestinal aGvHD-free and relapse-free survival by Day +180 (HR= 0.56, 95% CI: 0.37, 0.86; p = 0.0043), and for Grade C-D aGvHD-free (with any organ involvement) survival at Day +180 (HR: 0.59, 95% CI: 0.39, 0.91; p = 0.0204).¹ As well as, no related variations in security profile between the vedolizumab and placebo arms have been noticed, and no new security alerts have been recognized. Therapy-related adversarial occasions have been reported in 24.8% versus 28.4%, and therapy associated severe adversarial occasions in 8.5% versus 6.5% of sufferers handled with placebo versus vedolizumab, respectively. The commonest adversarial occasions of particular curiosity have been hypersensitivity reactions (placebo 82.4%, vedolizumab 79.3%), severe infections (placebo 67.3%, vedolizumab 74.0%), and liver damage (placebo 41.8%, vedolizumab 40.2%).¹

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“These outcomes have superior our understanding of vedolizumab, at present indicated for IBD, in one other crucial GI inflammatory situation,” mentioned Chinwe Ukomadu, M.D., Ph.D., Head, Gastroenterology Therapeutic Space Unit at Takeda. “Our Section 3 research within the prevention of decrease GI aGvHD is the most recent instance of Takeda’s dedication to advancing the science of vedolizumab, furthering the understanding of its mechanism of motion, and exploring new methods to assist sufferers.”

Intestinal aGvHD can happen after stem cell transplantation when the immune cells of the donor (the graft) take into account the recipient’s physique (the host) as international and assault the organs and tissue.² Intestinal aGvHD ends in the vast majority of morbidity and mortality related to GvHD. Efficient prevention of aGvHD, particularly with decrease intestinal involvement, has been an essential therapy objective for physicians when sufferers are present process allo-HSCT.³

Concerning the GRAPHITE Examine

GRAPHITE (vedolizumab-3035) is a randomized, double-blind, placebo managed research designed to guage the usage of vedolizumab as prophylaxis of intestinal aGvHD in individuals who obtain allo-HSCT as therapy for a hematologic malignancy or myeloproliferative dysfunction from an unrelated donor.¹ The research enrolled 333 sufferers who have been randomly assigned in a 1:1 ratio to one in all two therapy teams receiving both an intravenous infusion of vedolizumab 300 mg or placebo on days -1 (earlier than allo-HSCT), and on days +13, +41, +69, +97, +125, and +153 following allo-HSCT, alongside a background GvHD prophylaxis routine. The general time of participation within the research was 12 months.⁴

About vedolizumab (Entyvio^®)

Vedolizumab is a gut-selective anti-lymphocyte remedy and is accepted in each intravenous (IV) and subcutaneous (SC) formulations (approvals fluctuate by market; vedolizumab will not be at present accepted within the SC formulation within the U.S.).^5,6 It’s a humanized monoclonal antibody designed to particularly antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), however not vascular cell adhesion molecule 1 (VCAM-1).⁷ MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.⁸ The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.⁷ These cells have been proven to play a job in mediating the inflammatory course of in ulcerative colitis (UC) and Crohn’s illness (CD).^7,9,10 By inhibiting alpha4beta7 integrin, vedolizumab might restrict the power of sure white blood cells to infiltrate intestine tissues.⁷

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Vedolizumab is accepted for the therapy of grownup sufferers with reasonably to severely lively UC and CD, who’ve had an insufficient response with, misplaced response to, or have been illiberal to both typical remedy or a tumor necrosis factor-alpha (TNFα)-antagonist.^5,6 Vedolizumab IV has been granted advertising authorization in over 70 international locations, together with the US and European Union, with greater than 1,000,000 affected person years of publicity so far.¹¹ Vedolizumab SC has been granted advertising authorization within the European Union and over 50 international locations.

Takeda’s Dedication to Transplantation

Transplants are valuable, life-saving interventions, however severe post-transplant situations, together with cytomegalovirus (CMV) and GvHD, current vital challenges for transplant recipients. At Takeda, we acknowledge that the prevention, prognosis, and administration of post-transplant situations are critically essential, but typically ignored, aspects of transplant drugs. We’re pushed by these vital unmet must develop transformative therapies for transplant sufferers world wide.

Takeda’s Dedication to Gastroenterology

We consider that gastrointestinal (GI) and liver illnesses are usually not simply life disrupting situations, however illnesses that may impression a affected person’s high quality of life.^{Past a elementary want for efficient therapy choices, we perceive that enhancing sufferers’ lives additionally will depend on their wants being acknowledged. With practically 30 years of expertise in gastroenterology, Takeda has made vital strides in addressing affected person wants with remedies for inflammatory bowel illness (IBD), acid-related illnesses, brief bowel syndrome (SBS), and motility issues. We’re making vital strides towards closing the hole on new areas of unmet want. Along with researchers, affected person teams and extra, we’re working to advance scientific analysis and medical drugs in GI.}

Therapeutic Indications for vedolizumab

Ulcerative Colitis

Vedolizumab is indicated for the therapy of grownup sufferers with reasonably to severely lively ulcerative colitis who’ve had an insufficient response with, misplaced response to, or have been illiberal to both typical remedy or a tumor necrosis factor-alpha (TNFα) antagonist.

Crohn’s Illness

Vedolizumab is indicated for the therapy of grownup sufferers with reasonably to severely lively Crohn’s illness who’ve had an insufficient response with, misplaced response to, or have been illiberal to both typical remedy or a tumor necrosis factor-alpha (TNFα) antagonist.

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Pouchitis

Vedolizumab IV is indicated within the EU for the therapy of grownup sufferers with reasonably to severely lively continual pouchitis, who’ve undergone proctocolectomy and ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) and have had an insufficient response with or misplaced response to antibiotic remedy.

Necessary Security Info for vedolizumab

Contraindications

Hypersensitivity (resembling dyspnea, bronchospasm, urticaria, flushing and elevated coronary heart charge) to the lively substance or to any of the excipients.

Particular Warnings and Particular Precautions for Use

Intravenous vedolizumab must be administered by a healthcare skilled ready to handle hypersensitivity reactions, together with anaphylaxis, in the event that they happen. Acceptable monitoring and medical assist measures must be out there for speedy use when administering intravenous vedolizumab. Observe sufferers throughout infusion and till the infusion is full.

Infusion-related reactions and Hypersensitivity Reactions

In medical research, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the bulk being gentle to average in severity. If a extreme IRR, anaphylactic response, or different extreme response happens, administration of vedolizumab have to be discontinued instantly and acceptable therapy initiated (e.g., epinephrine and antihistamines). If a light to average IRR happens, the infusion charge could be slowed or interrupted and acceptable therapy initiated (e.g., epinephrine and antihistamines). As soon as the gentle or average IRR subsides, proceed the infusion. Physicians ought to take into account pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) previous to the following infusion for sufferers with a historical past of gentle to average IRR to vedolizumab, to be able to decrease their dangers.

Injection Website Reactions (subcutaneous vedolizumab)

No clinically related variations within the general security profile and adversarial occasions have been noticed in sufferers who acquired subcutaneous vedolizumab in comparison with the security profile noticed in medical research with intravenous vedolizumab except injection website reactions (with subcutaneous administration solely). Injection-site reactions have been gentle or average in depth, and none have been reported as severe.

Infections

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Vedolizumab is a gut-selective integrin antagonist with no recognized systemic immunosuppressive exercise. Physicians ought to concentrate on the potential elevated danger of opportunistic infections or infections for which the intestine is a defensive barrier. Vedolizumab therapy is to not be initiated in sufferers with lively, extreme infections resembling tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic infections till the infections are managed, and physicians ought to take into account withholding therapy in sufferers who develop a extreme an infection whereas on continual therapy with vedolizumab. Warning must be exercised when contemplating the usage of vedolizumab in sufferers with a managed continual extreme an infection or a historical past of recurring extreme infections. Sufferers must be monitored intently for infections earlier than, throughout and after therapy. Earlier than beginning therapy with vedolizumab, screening for tuberculosis could also be thought-about in line with native follow. Some integrin antagonists and a few systemic immunosuppressive brokers have been related to progressive multifocal leukoencephalopathy (PML), which is a uncommon and sometimes deadly opportunistic an infection brought on by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut-homing lymphocytes, vedolizumab exerts an immunosuppressive impact particular to the intestine. No systemic immunosuppressive impact was famous in wholesome topics. Healthcare professionals ought to monitor sufferers on vedolizumab for any new onset or worsening of neurological indicators and signs, and take into account neurological referral in the event that they happen. If PML is suspected, therapy with vedolizumab have to be withheld; if confirmed, therapy have to be completely discontinued. Typical indicators and signs related to PML are numerous, progress over days to weeks, and embrace progressive weak spot on one aspect of the physique, clumsiness of limbs, disturbance of imaginative and prescient, and adjustments in considering, reminiscence, and orientation resulting in confusion and persona adjustments. The development of deficits normally results in loss of life or extreme incapacity over weeks or months.

Malignancies

The danger of malignancy is elevated in sufferers with ulcerative colitis and Crohn’s illness. Immunomodulatory medicinal merchandise might enhance the chance of malignancy.

Prior and concurrent use of organic merchandise

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No vedolizumab medical trial knowledge can be found for sufferers beforehand handled with natalizumab. No medical trial knowledge for concomitant use of vedolizumab with biologic immunosuppressants can be found. Subsequently, the usage of vedolizumab in such sufferers will not be really helpful.

Vaccinations

Previous to initiating therapy with vedolizumab all sufferers must be introduced updated with all really helpful immunizations. Sufferers receiving vedolizumab might obtain non-live vaccines (e.g., subunit or inactivated vaccines) and will obtain stay vaccines provided that the advantages outweigh the dangers.

Hostile reactions embrace: nasopharyngitis, headache, arthralgia, higher respiratory tract an infection, bronchitis, influenza, sinusitis, cough, oropharyngeal ache, nausea, rash, pruritus, again ache, ache in extremities, pyrexia, fatigue, injection website reactions and anaphylaxis.

Please seek the advice of together with your native regulatory company for accepted labeling in your nation.

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

For U.S. audiences, please see the complete Prescribing Info, together with Medicine Information for ENTYVIO^® IV.

About Takeda

Takeda is a worldwide, values-based, R&D-driven biopharmaceutical chief headquartered in Japan, dedicated to find and ship life-transforming remedies, guided by our dedication to sufferers, our folks and the planet. Takeda focuses its R&D efforts on 4 therapeutic areas: Oncology, Uncommon Genetics and Hematology, Neuroscience, and Gastroenterology (GI), with experience in immune and inflammatory illnesses. We additionally make focused R&D investments in Plasma-Derived Therapies and Vaccines. We’re specializing in creating extremely modern medicines that contribute to creating a distinction in folks’s lives by advancing the frontier of recent therapy choices and leveraging our enhanced collaborative R&D engine and capabilities to create a sturdy, modality-diverse pipeline. Our workers are dedicated to enhancing high quality of life for sufferers and to working with our companions in well being care in roughly 80 international locations and areas. For extra data, go to https://www.takeda.com.

Necessary Discover

For the needs of this discover, “press launch” means this doc, any oral presentation, any query and reply session and any written or oral materials mentioned or distributed by Takeda Pharmaceutical Firm Restricted (“Takeda”) concerning this launch. This press launch (together with any oral briefing and any question-and-answer in reference to it) will not be supposed to, and doesn’t represent, characterize or kind a part of any provide, invitation or solicitation of any provide to buy, in any other case purchase, subscribe for, trade, promote or in any other case get rid of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or different securities are being supplied to the general public by the use of this press launch. No providing of securities shall be made in the US besides pursuant to registration underneath the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press launch is being given (along with any additional data which can be offered to the recipient) on the situation that it’s to be used by the recipient for data functions solely (and never for the analysis of any funding, acquisition, disposal or some other transaction). Any failure to adjust to these restrictions might represent a violation of relevant securities legal guidelines.

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The businesses through which Takeda straight and not directly owns investments are separate entities. On this press launch, “Takeda” is usually used for comfort the place references are made to Takeda and its subsidiaries normally. Likewise, the phrases “we”, “us” and “our” are additionally used to discuss with subsidiaries normally or to those that work for them. These expressions are additionally used the place no helpful goal is served by figuring out the actual firm or firms.

Ahead-Trying Statements

This press launch and any supplies distributed in reference to this press launch might include forward-looking statements, beliefs or opinions concerning Takeda’s future enterprise, future place and outcomes of operations, together with estimates, forecasts, targets and plans for Takeda. With out limitation, forward-looking statements typically embrace phrases resembling “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “goals”, “intends”, “ensures”, “will”, “might”, “ought to”, “would”, “might” “anticipates”, “estimates”, “initiatives” or related expressions or the adverse thereof. These forward-looking statements are based mostly on assumptions about many essential components, together with the next, which might trigger precise outcomes to vary materially from these expressed or implied by the forward-looking statements: the financial circumstances surrounding Takeda’s international enterprise, together with common financial situations in Japan and the US; aggressive pressures and developments; adjustments to relevant legal guidelines and rules, together with international well being care reforms; challenges inherent in new product growth, together with uncertainty of medical success and selections of regulatory authorities and the timing thereof; uncertainty of business success for brand new and present merchandise; manufacturing difficulties or delays; fluctuations in curiosity and foreign money trade charges; claims or considerations concerning the security or efficacy of marketed merchandise or product candidates; the impression of well being crises, just like the novel coronavirus pandemic, on Takeda and its clients and suppliers, together with international governments in international locations through which Takeda operates, or on different aspects of its enterprise; the timing and impression of post-merger integration efforts with acquired firms; the power to divest belongings that aren’t core to Takeda’s operations and the timing of any such divestment(s); and different components recognized in Takeda’s most up-to-date Annual Report on Kind 20-F and Takeda’s different reviews filed with the U.S. Securities and Trade Fee, out there on Takeda’s web site at: https://www.takeda.com/buyers/sec-filings/ or at www.sec.gov. Takeda doesn’t undertake to replace any of the forward-looking statements contained on this press launch or some other forward-looking statements it might make, besides as required by legislation or inventory trade rule. Previous efficiency will not be an indicator of future outcomes and the outcomes or statements of Takeda on this press launch will not be indicative of, and are usually not an estimate, forecast, assure or projection of Takeda’s future outcomes.

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Medical data

This press launch comprises details about merchandise that will not be out there in all international locations, or could also be out there underneath completely different emblems, for various indications, in several dosages, or in several strengths. Nothing contained herein must be thought-about a solicitation, promotion or commercial for any prescribed drugs together with those underneath growth.

References

¹ Chen YB, Mohty M, Zeiser R, et al. Vedolizumab for Prophylaxis of Decrease Gastrointestinal (GI) Acute Graft-versus-Host Illness (aGvHD) After Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) From Unrelated Donors: Outcomes of A Section 3, Randomized, Double-Blind, Placebo-Managed, Multicenter Examine (GRAPHITE). Summary #LBA2. Introduced on the Transplantation & Mobile Remedy Conferences of the American Society for Transplantation and Mobile Remedy (ASTCT) and the Heart for Worldwide Blood & Marrow Transplant Analysis (CIBMTR) 2023.

² Naserian S, Leclerc M, Shamdani S, et al. Present Preventions and Remedies of aGVHD: From Pharmacological Prophylaxis to Revolutionary Therapies. Entrance Immunol. 2020;11:607030.

³ Chen YB, Shah NN, Renteria AS, et al. Vedolizumab for prevention of graft-versus-host illness (GvHD) after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3(23):4136-4146.

⁴ Vedolizumab within the Prophylaxis of Intestinal Acute Graft Versus Host Illness (aGVHD) in Members Present process Allogeneic Hematopoietic Stem Cell (Allo-HSCT) Transplantation. Accessible at: https://clinicaltrials.gov/ct2/present/NCT03657160 Final up to date: November 3 , 2022. Final accessed: February 2023.

⁵ Entyvio EPAR _ 29/09/2022 Entyvio – EMEA/H/C/002782 – II/0070/G_ European Medicines Company – Entyvio _ Annex I Abstract of product traits. Committee For Medicinal Merchandise For Human Use. Accessible at: https://www.ema.europa.eu/en/medicines/human/EPAR/entyvio. Final up to date: October 2022. Final accessed: February 2023.

⁶ Entyvio Prescribing Info. Accessible at: https://common.takedapharm.com/ENTYVIOPI. Final up to date: June 2022. Final accessed: February 2023.

⁷ Soler D, Chapman T, Yang LL, et al. The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in growth for inflammatory bowel illnesses. J Pharmacol Exp Ther. 2009;330:864-875.

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⁸ Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and related lymphoid tissue. Am J Pathol. 1997;151:97‑110.

⁹ Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles within the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298‑1312.

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

¹¹ Takeda knowledge on file (VV-SUP-91507): Vedolizumab Affected person Publicity from Advertising Expertise. 2021.

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