Additional subgroup analysis shows subcutaneous formulation of vedolizumab achieves significantly higher clinical remission rates to placebo in anti-TNFα-naïve patients

OSAKA, Japan I October 22, 2018 I 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%).1 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 responseǂ (64.2% vs. 28.6%; p<0.001). Vedolizumab SC was also numerically higher to placebo in achieving durable clinical remissionǂǂ (15.1% vs. 5.4%; p=0.076) and corticosteroid-free clinical remissionǂǂǂ (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.1 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).1

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).1

“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.1,2

* 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.  

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.2,3,4

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).5 Both UC and CD are chronic, relapsing, remitting, inflammatory conditions of the gastrointestinal (GI) tract that are often progressive in nature.6,7 UC only involves the large intestine as opposed to CD which can affect any part of the GI tract from mouth to anus.8,9 CD can also affect the entire thickness of the bowel wall, while UC only involves the innermost lining of the large intestine.8 UC commonly presents with symptoms of abdominal discomfort, loose bowel movements, including blood or pus.8,10 CD commonly presents with symptoms of abdominal pain, diarrhea, and weight loss.6 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.8,11,12

About Entyvio® (vedolizumab)

Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation.13 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).14 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.15 The alpha4beta7 integrin is expressed on a subset of circulating white blood cells.14 These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis (UC) and Crohn’s disease (CD).14,16,17 By inhibiting alpha4beta7 integrin, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.14

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.18

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.13

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.13

For U.S. audiences, please see the full Prescribing Information including Medication Guide for ENTYVIO®.19

For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO®.1

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/.

References

1 Sandborn WJ, Baert F, Danese S, et al. Subcutaneous vedolizumab as maintenance therapy for ulcerative colitis. Presented at the United European Gastroenterology Week congress, Vienna, Austria. #LB03.

2 Efficacy and safety of vedolizumab subcutaneously (SC) as maintenance therapy in ulcerative colitis. Available at: https://clinicaltrials.gov/ct2/show/NCT02611830 Last accessed October 2018.

3 Efficacy and safety of vedolizumab subcutaneous (SC) as maintenance therapy in Crohn’s disease. Available at: https://clinicaltrials.gov/ct2/show/NCT02611817 Last accessed October 2018.

4 Vedolizumab subcutaneous long-term open-label extension study. Available at: https://clinicaltrials.gov/ct2/show/NCT02620046 Last accessed October 2018.

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

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

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

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

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

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

11 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.

12 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.

13 Entyvio® Summary of Product Characteristics. March 2018.

14 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.

15 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.

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

17 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.

18 Takeda. 2018. Data on file.

19 Entyvio (vedolizumab) Prescribing Information. February 2018

SOURCE: Takeda Pharmaceutical Co