Investigational Subcutaneous Formulation of Vedolizumab Achieves and Maintains Clinical Remission and Mucosal Healing at Week 52 in Patients with Moderately to Severely Active Ulcerative Colitis

Takeda Pharmaceutical Company Limited [TSE:4502] (“Takeda”) today announced results from the phase 3 VISIBLE 1 clinical trial evaluating the efficacy and safety of an investigational subcutaneous (SC) formulation of the gut-selective biologic vedolizumab for maintenance therapy in adult patients with moderately to severely active ulcerative colitis (UC) who achieved clinical response^* at week 6 following two doses of open-label vedolizumab intravenous (IV) induction therapy. At week 52, a statistically significant proportion of patients receiving vedolizumab SC achieved clinical remission^** compared to patients receiving placebo (46.2% vs. 14.3%; p<0.001). A similar rate of clinical remission was observed in the vedolizumab IV reference arm (42.6%). These results were presented at the 2018 United European Gastroenterology (UEG) Week congress in Vienna, Austria.

“The VISIBLE 1 results highlight that the investigational subcutaneous formulation of vedolizumab helped patients with moderately to severely active ulcerative colitis achieve and maintain clinical remission, mucosal healing and durable clinical response, after responding to vedolizumab IV induction therapy. These data indicate that the subcutaneous formulation of vedolizumab had an efficacy and safety profile similar to the IV reference arm, and further add to the collective dataset for vedolizumab in ulcerative colitis,” said Professor William J. Sandborn, lead investigator for the VISIBLE 1 trial and Director of the Inflammatory Bowel Disease Center at UC San Diego.

Furthermore, vedolizumab SC was statistically superior to placebo in key secondary endpoints of mucosal healing^*** (56.6% vs. 21.4%; p<0.001) and durable clinical response^ǂ (64.2% vs. 28.6%; p<0.001). Vedolizumab SC was also numerically higher to placebo in achieving durable clinical remission^ǂǂ (15.1% vs. 5.4%; p=0.076) and corticosteroid-free clinical remission^ǂǂǂ (28.9% vs. 8.3%; p=0.067), with these results not being of statistical significance. Similar findings were observed for these endpoints in the vedolizumab IV reference arm. Additionally, a subgroup analysis showed clinical remission rates were significantly higher with vedolizumab SC compared to placebo in anti-tumor necrosis factor-alpha (TNFα)-naïve (53.7% vs. 18.9%; p<0.001) and anti-TNFα-failure patients (33.3% vs. 5.3%; p=0.023).

Adverse event rates, including severe adverse events and infections, were similar in the vedolizumab SC and IV groups. Injection-site reactions were mild and experienced by 9.4% of patients in the vedolizumab SC treatment group (vs. 0 in the placebo group), with none leading to treatment discontinuation. The rate of anti-vedolizumab antibodies (AVAs) was similar between the vedolizumab SC and IV groups (5.7% and 5.6%, respectively).

“These results mark an important milestone for Takeda in our efforts to better meet the needs of patients with inflammatory bowel disease. We hope to make the subcutaneous formulation of vedolizumab available to provide more choice for patients and their physicians. The patient’s experience is very important to us, and we are committed to providing physicians with treatment options that suit the individual needs and preferences of their patients, whether that is intravenous or subcutaneous,” said Jeff Bornstein, Executive Medical Director, Takeda.

VISIBLE 1 is a pivotal phase 3, randomized, double-dummy, double-blind, placebo-controlled study, with a vedolizumab IV reference arm, to evaluate the safety and efficacy of an investigational SC formulation of vedolizumab as maintenance therapy in adult patients with moderately to severely active UC who have achieved clinical response at week 6 following two doses of open-label vedolizumab IV therapy at weeks 0 and 2. The study enrolled 383 patients, all of whom had inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or anti-TNFα therapy prior to being enrolled. Patients who achieved clinical response at week 6 (n=216, 56.4%) were randomized into one of three treatment groups, vedolizumab SC 108 mg and placebo IV (n=106), vedolizumab IV 300 mg and placebo SC (n=54), or placebo SC and placebo IV (n=56). Subcutaneous doses were administered every two weeks and intravenous doses were administered every eight weeks.

* 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.

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

*** Mucosal healing is defined as a Mayo endoscopic subscore of ≤1 point.

ǂ Durable clinical response is defined as clinical response at weeks 6 and 52, where 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.

ǂǂ Durable clinical remission is defined as clinical remission at weeks 6 and 52.

ǂǂǂ Corticosteroid-free clinical remission is defined as patients using oral corticosteroids at baseline (week 0) who have discontinued oral corticosteroids and are in clinical remission at week 52. PBO: n=24, VDZ SC: n=45, VDZ IV: n=21.

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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 patients which includes two randomized, double-blind, placebo-controlled studies examining the percentage of participants achieving clinical remission at week 52 in UC and CD, respectively, and an open-label extension study to determine the long-term safety and efficacy of vedolizumab SC consisting of patients who have completed one of the randomized clinical trials.

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). Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal (GI) tract that are often progressive in nature. UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus. CD can also affect the entire thickness of the bowel wall, while UC only involves the innermost lining of the large intestine. UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus. CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss. 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.

About Entyvio ^® (vedolizumab)
Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation. 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). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD). By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.

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. Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with over 200,000 patient years of exposure to date.

Therapeutic Indications

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 equipped 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 all 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 on 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. Caution should be exercised when considering the use of vedolizumab in these patients. 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, and fatigue.

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) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Around 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries.

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

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