Takeda Receives Complete Response Letter from U.S. FDA for the Investigational Subcutaneous Formulation of ENTYVIO^® (vedolizumab) as a Maintenance Therapy in Adults with Moderate to Severe Ulcerative Colitis

• FDA communication is unrelated to the intravenous formulation of Entyvio, which has been used by more than 150,000 patients since its approval in 2014^[i],[ii]

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that it has received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) in response to the submission of a Biologics License Application (BLA) for the approval of an investigational subcutaneous formulation of Entyvio^® (vedolizumab) for maintenance therapy in adults with moderate to severe ulcerative colitis (UC).

Takeda is assessing the details of the letter, gathering information needed to resolve the FDA’s questions, and will work closely with the FDA on a path to approval. In its letter, the FDA posed questions unrelated to the clinical data and conclusions from the pivotal trial supporting the BLA.

Takeda strongly believes in the potential benefit that subcutaneous Entyvio can bring to patients who live with moderate to severe UC. The company remains committed to working with the FDA to meet patient needs with this important route of administration.

Since intravenous (IV) Entyvio was approved by the U.S. FDA in 2014 for patients with moderate to severe UC and Crohn’s disease, clinical trials and other evidence have continued to support its well-established safety and efficacy profile.^[i],[iii] Entyvio IV has been granted marketing authorization in more than 60 countries, including the U.S. and European Union; in the U.S. more than 150,000 patients have used Entyvio.^[i],[ii]

“At Takeda, we know how important it is to provide physicians and patients with choices, and we continue to drive innovation and development to meet their needs,” said Asit Parikh, MD, PhD, head of Takeda’s Gastroenterology Therapeutic Area Unit. “We’re committed to the development of the subcutaneous formulation of Entyvio, and look forward to working closely with the FDA to determine next steps.”

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).^[iv] Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal tract that are often progressive in nature.^[v],[vi] UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.^[vii],[viii] CD can also affect the entire thickness of the bowel wall, while UC only involves the innermost lining of the large intestine.^[vi],[vii] UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus.^[vii],[ix] CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.^[v] The cause of UC or CD is not fully understood; however, recent research suggests heredity, genetics, environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to UC or CD.^{[vii],[x],[xi]}

About Entyvio^® (vedolizumab)

Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.^[ii] It is a humanized monoclonal antibody designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal address in cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1).^[xii] MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.^[xiii] The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.^[xii] These cells have been shown to play a role in mediating the inflammatory process in UC and CD.^{[xii],[xiv],[xv]} By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.^[xii]

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.^[ii]

U.S. INDICATIONS: ENTYVIO (vedolizumab) FOR INTRAVENOUS USE

Adult Ulcerative Colitis (UC)

ENTYVIO (vedolizumab) is indicated in adult patients with moderately to severely active UC who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving endoscopic appearance of the mucosa, and achieving corticosteroid-free remission.

Adult Crohn’s Disease (CD)

ENTYVIO (vedolizumab) is indicated in adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids for achieving clinical response, achieving clinical remission, and achieving corticosteroid-free remission.

U.S. IMPORTANT SAFETY INFORMATION FOR ENTYVIO (VEDOLIZUMAB) FOR INTRAVENOUS USE

• 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 have occurred. Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed. If anaphylaxis or other serious allergic 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.
• Although no cases of PML have been observed in ENTYVIO clinical trials, JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death has occurred in patients treated with another integrin receptor antagonist. 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.

In the U.S., please see the accompanying full Prescribing Information including Medication Guide for ENTYVIO.

More information is available in the U.S. at www.ENTYVIOHCP.com.

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 more than 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, short bowel syndrome, 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, Rare Diseases, 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.

For more information, visit https://www.takeda.com.

About Takeda Pharmaceuticals U.S.A.

Takeda has maintained a strong and growing commitment to the United States for more than 50 years. On January 8, 2019, Takeda completed its acquisition of Shire, PLC, becoming a global, values-based, R&D-driven biopharmaceutical leader. In the U.S., Takeda employs more than 18,000 employees across multiple business units, and as of August 2019, is headquartered out of the greater Boston area.

Additionally, Takeda also has a research facility in San Diego, California, specialty products manufacturing facilities in Brooklyn Park, Minnesota and plasma fractionation manufacturing facilities in Covington, Georgia.

As one of the world’s leading biopharmaceutical companies, Takeda is committed to bringing Better Health and a Brighter Future to people worldwide. We aspire to bring our leadership in translating science into life-changing medicines to the next level, in our core focus areas; oncology, gastroenterology, neuroscience, rare diseases, plasma-derived therapies, and vaccines.

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References

[i] Data on file. Takeda Pharmaceuticals.

[ii] Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals.

[iii] Narula N, Peerani F, Meserve J, et al. Am J Gastroenterol. 2018;113:1345-1354.

[iv] Baumgart DC, Carding SR. Lancet. 2007;369:1627-1640.

[v] Baumgart DC, Sandborn WJ. Lancet. 2012;380:1590-1605.

[vi] Torres J, Billioud V, Sachar DB, et al. Inflamm Bowel Dis. 2012;18:1356-1363.

[vii] Ordas I, Eckmann L, Talamini M, et al. Lancet. 2012;380:1606-1619.

[viii] Feuerstein JD, Cheifetz AS. Mayo Clin Proc. 2017;92:1088-1103.

[ix] Sands BE. Gastroenterology. 2004;126:1518-1532.

[x] Henckaerts L, Pierik M, Joossens M, et al. Gut. 2007;56:1536-1542.

[xi] Kaser A, Zeissig S, Blumberg RS. Dig Dis. 2010;28:395-405.

[xii] Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330:864-875.

[xiii] Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151:97-110.

[xiv] Eksteen B, Liaskou E, Adams DH. Inflamm Bowel Dis. 2008;14:1298‑1312.

[xv] Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10:1437-1444.