Takeda Announces FDA Acceptance of BLA Resubmission for Investigational Subcutaneous Administration of Entyvio® (vedolizumab) for Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis

Rhea-AI Summary

Takeda announced the U.S. FDA's acceptance of its Biologics License Application (BLA) resubmission for the investigational subcutaneous administration of Entyvio (vedolizumab) for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC). This resubmission addresses FDA feedback from a 2019 Complete Response Letter (CRL). The resubmission includes additional data on the SC administration of Entyvio, which is currently available in intravenous form. Takeda expects a decision by the end of 2023. The pivotal VISIBLE 1 trial, assessing the SC formulation, involved 216 adult patients and demonstrated a primary endpoint of clinical remission at week 52. The SC formulation aims to offer patients an alternative to IV infusion, enhancing treatment options.

Positive

• The FDA accepted Takeda's BLA resubmission for Entyvio SC, indicating progress toward approval.
• The resubmission is supported by additional data addressing prior FDA concerns.
• Entyvio SC offers patients an alternative to intravenous administration, potentially improving patient compliance and convenience.
• The pivotal VISIBLE 1 trial successfully demonstrated efficacy, with a focus on clinical remission at week 52.

Negative

• The FDA's previous CRL in December 2019 indicated unresolved concerns, potentially delaying market entry.
• The approval timeline remains uncertain, pending FDA decision expected by the end of 2023.

OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food and Drug Administration (FDA) has accepted for review its Biologics License Application (BLA) resubmission for the investigational subcutaneous (SC) administration of Entyvio^® (vedolizumab) for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC) after induction therapy with Entyvio intravenous. The resubmission is intended to address FDA feedback in a December 2019 Complete Response Letter (CRL).

“Takeda has remained committed to the pursuit of a subcutaneous administration for Entyvio in the U.S. so that patients might have a choice between receiving Entyvio maintenance therapy via intravenous infusion by a health care professional or administering it themselves with a single-dose injection – whichever suits their medical and personal needs. This resubmission is a major step forward in delivering on that commitment,” said Vijay Yajnik, M.D., Ph.D., vice president, head of U.S. Medical for Gastroenterology, Takeda. “We have great confidence in the future of Entyvio SC and strongly believe that offering a SC formulation can help meet the varied needs of patients who live with moderate to severe ulcerative colitis, pending approval.”

Since receiving the CRL Takeda has worked closely with the FDA to address the Agency’s feedback; this resubmission package includes additional data collected to investigate the use of subcutaneous administration of Entyvio. The contents of the letter were unrelated to the intravenous (IV) formulation of Entyvio, the clinical safety and efficacy data, and conclusions from the pivotal VISIBLE 1 trial supporting the Entyvio SC BLA.

VISIBLE 1 assessed the safety and efficacy of a SC formulation of Entyvio as maintenance therapy in 216 adult patients with moderately to severely active UC who achieved clinical response* at week 6 following two doses of open-label vedolizumab intravenous therapy at weeks 0 and 2.¹ The primary endpoint was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1.¹

Takeda expects a decision from the FDA by the end of 2023.

*Clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from baseline (week 0) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.1

About Entyvio^® (vedolizumab)

Vedolizumab is a biologic therapy and is approved in intravenous (IV) and subcutaneous (SC) formulations (approvals vary by market; vedolizumab is not currently approved in the SC formulation in the U.S.).^2,3 Vedolizumab SC has been granted marketing authorization in the European Union and more than 50 countries. Vedolizumab IV has been granted marketing authorization in more than 70 countries, including the United States and European Union, with more than 1,000,000 patient years of exposure to date.⁴ 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).⁵ MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.⁶ The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.⁵ These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).^5,7,8 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.⁵

IMPORTANT SAFETY INFORMATION FOR ENTYVIO IV

• ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients.
• Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.
• Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice.
• Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm³ and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently.
• There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury.
• Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.
• Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

Please see accompanying full U.S. Prescribing Information, including Medication Guide.

INDICATIONS FOR IV USE

Adult Ulcerative Colitis (UC)

ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC.

Adult Crohn’s Disease (CD)

ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.

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).⁹ Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract.^10,11 UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.^12,13 CD can also affect the entire thickness of the bowel wall, while UC only involves the innermost lining of the large intestine.^12,13 UC can present with symptoms of abdominal discomfort or loose bowel movements, including blood.^12,14 CD can present with symptoms of abdominal pain, diarrhea, and weight loss.¹⁰ The cause of UC or CD is not fully understood; however, research suggests that an interplay between environmental factors, genetics, and intestinal microbiota may contribute to the development of UC or CD.^12,15,16

Takeda’s Commitment to Gastroenterology

We believe that gastrointestinal (GI) and liver diseases are not just life disrupting conditions, but diseases that can impact a patient’s quality of life. 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 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 need. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI.

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 https://www.takeda.com.

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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, 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.

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

1	Sandborn WJ, Baert F, Danese S, et al. Gastroenterology. 2020;158(3):562-572.
2	Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. Last updated: June 2022. Last accessed: January 2023.
3	Entyvio Summary of Product Characteristics (SmPC). Available at: https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-product-information_en.pdf. Last updated: October 2022. Last accessed: February 2023.
4	Takeda data on file (VV-SUP-91507): Vedolizumab Patient Exposure from Marketing Experience. 2021.
5	Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330:864-875.
6	Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151:97‑110.
7	Eksteen B, Liaskou E, Adams DH. Inflamm Bowel Dis. 2008;14:1298‑1312.
8	Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10:1437-1444.
9	Baumgart DC, Carding SR. Lancet. 2007;369:1627-1640.
10	Baumgart DC, Sandborn WJ. Lancet. 2012;380:1590-1605.
11	Torres J, Billioud V, Sachar DB, et al. Inflamm Bowel Dis. 2012;18:1356-1363.
12	Ordas I, Eckmann L, Talamini M, et al. Lancet. 2012;380:1606-1619.
13	Feuerstein JD, Cheifetz AS. Mayo Clin Proc. 2017;92:1088-1103.
14	Sands BE. Gastroenterology. 2004;126:1518-1532.
15	Kobayashi T, Siegmund B, Le Berre C, et al. Nat Rev Dis Primers. 2020;6(74).
16	Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Lancet. 2017; 389(10080):1741-1755.

 

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Media:

Japanese Media

Jun Saito

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+81 3-3278-2325

Media Outside Japan

Amy McCarthy

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+1 781-496-7761

Source: Takeda Pharmaceutical Company Limited

FAQ

What did Takeda announce regarding Entyvio on April 27, 2023?

Takeda announced the FDA's acceptance of its BLA resubmission for the subcutaneous administration of Entyvio for ulcerative colitis treatment.

What is the expected timeline for FDA's decision on Entyvio SC?

Takeda expects a decision from the FDA by the end of 2023 regarding the Entyvio SC BLA.

What is the primary focus of the pivotal VISIBLE 1 trial for Entyvio?

The primary focus was on achieving clinical remission at week 52 in adults with moderately to severely active ulcerative colitis.

What are the advantages of the subcutaneous formulation of Entyvio?

The subcutaneous formulation offers patients an alternative to intravenous administration, enhancing convenience and potential compliance.

What were the concerns raised by the FDA regarding Entyvio in the past?

The FDA issued a Complete Response Letter in December 2019, indicating unresolved issues that needed to be addressed in the resubmission.