U.S. Food & Drug Administration Accepts Takeda’s Biologics License Application for a Subcutaneous Formulation of Vedolizumab (Entyvio®) for Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis

• An additional treatment modality would provide more flexibility in how patients receive vedolizumab, a biologic with a gut-selective mode of action
• Vedolizumab set to be the only maintenance therapy to offer the option of intravenous or subcutaneous formulations for patients with ulcerative colitis

OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food & Drug Administration (FDA) has accepted for review a Biologics License Application (BLA) for a subcutaneous (SC) formulation of vedolizumab for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC). Takeda proposes to make vedolizumab SC available in both pre-filled syringe and pen options.

“Acceptance of this regulatory submission for review brings us one step closer to our goal of better meeting the diverse needs of patients with ulcerative colitis in the U.S. The availability of a subcutaneous option for maintenance therapy with vedolizumab, in addition to the currently approved intravenous formulation, would provide physicians and patients with greater flexibility on route of administration, if approved,” said Uthra Sundaram, Senior Vice President, GI Business Unit, Takeda Pharmaceuticals U.S.A., Inc.

The application is based on the pivotal VISIBLE 1 phase 3 study, which assessed the safety and efficacy of a SC formulation of vedolizumab 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 (IV) therapy at weeks 0 and 2.¹ The results of VISIBLE 1 were presented at the 2018 United European Gastroenterology (UEG) Week Congress in Vienna, Austria.

In evaluating the primary endpoint of VISIBLE 1, a statistically significant proportion of patients receiving vedolizumab SC 108 mg maintenance therapy administered every two weeks achieved clinical remission** compared to patients receiving placebo (46.2% vs. 14.3%; p<0.001) at week 52. A similar rate of clinical remission was observed in the vedolizumab IV 300 mg reference arm (42.6%) at week 52. Furthermore, adverse event rates, including severe adverse events and infections, were similar between the SC and IV groups at week 52. Injection-site reactions were generally mild and experienced by 10.4% of patients in the vedolizumab SC treatment arm (vs. 0% in the placebo group), with none leading to treatment discontinuation.^1,2

“The VISIBLE 1 study provides us with important knowledge on the characterization of the efficacy and safety profile for the investigational subcutaneous formulation of vedolizumab,” said Karen Lasch, M.D., Medical Head, Specialty GI, U.S. Medical Office, Takeda. “Takeda is deeply committed to bringing innovative medicines and treatment modalities to patients living with gastrointestinal diseases.”

* 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.^3

** Clinical remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.^3

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

VISIBLE 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 percentage of participants achieving clinical remission at week 52, and an open-label extension study to determine the long-term safety and efficacy of vedolizumab SC.^3,4,5

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).⁶ Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract that are often progressive in nature.^7,8 UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.^9,10 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.^9,11 CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.⁷ 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. ^9,12,13

About Entyvio^® (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.¹⁴ 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 IV 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.¹⁴ Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 260,000 patient years of exposure to date.²

Therapeutic Indications (vedolizumab IV)

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

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

Special warnings and special precautions for use
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 vedolizumab. Observe patients during infusion and until the infusion is complete.

Infusion-related 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. Although no systemic immunosuppressive effect was noted in healthy subjects, the effects on systemic immune system function in patients with inflammatory bowel disease are not known. 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 and anaphylaxis.

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

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

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

Takeda’s Commitment to Gastroenterology
Gastrointestinal (GI) diseases can be complex, debilitating and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for over 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associated with high unmet need, such as inflammatory bowel disease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well as scientific advancements through microbiome therapies.

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, Gastroenterology (GI), Neuroscience, and Rare 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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References

^1 Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the VISIBLE 1 phase 3 trial. United European Gastroenterology J. 2018;6(Supplement 1).

^2 Takeda Data on File. 2019.

^3 Efficacy and safety of vedolizumab subcutaneously (SC) as maintenance therapy in ulcerative colitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02611830. Last updated: August 27, 2018. Last accessed: April 2019.

^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: December 24, 2018. Last accessed: April 2019.

^5 Vedolizumab subcutaneous long-term open-label extension study. Available at: https://clinicaltrials.gov/ct2/show/NCT02620046. Last updated December 24, 2018. Last accessed: April 2019.

^6 Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.

^7 Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605.

^8 Torres J, Billioud V, Sachar DB, et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18:1356-1363.

^9 Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380:1606-1619.

^10 Feuerstein JD, Cheifetz AS. Crohn’s disease: Epidemiology, diagnosis and management. Mayo Clin Proc. 2017;92:1088-1103.

^11 Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126:1518-1532.

^12 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.

^13 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.

^14 Entyvio Prescribing Information. Available at: https://general.takedapharm.com/ENTYVIOPI. Last updated: February 2018. Last accessed: April 2019.

^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.

^17 Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its roles in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14:1298-1312.

^18 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.