Data Published in the New England Journal of Medicine for Vedolizumab, an Investigational New Drug from Takeda for Moderately to Severely Active Ulcerative Colitis and Crohn's Disease

OSAKA, Japan, Aug. 21, 2013 /PRNewswire/ -- Takeda Pharmaceutical Company Limited ("Takeda") today announced that results from two Phase 3 studies evaluating vedolizumab, an investigational humanized monoclonal antibody, for the treatment of adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), were published in the August 22, 2013 issue of the New England Journal of Medicine. Chronic and debilitating diseases, CD and UC are the two most common types of inflammatory bowel disease (IBD) and affect more than four million people worldwide, including approximately 1.4 million Americans and 2.2 million Europeans. Vedolizumab is designed to specifically antagonize the alpha4beta7 integrin, which is expressed on a subset of circulating white blood cells that have been shown to play a role in mediating the inflammatory process in CD and UC. 

"The publication of these study findings is important since the results support the potential for vedolizumab, if approved, to help manage symptoms in some patients for whom certain previous treatments have failed," said Brian Feagan, M.D., professor of medicine, epidemiology, and biostatistics at the University of Western Ontario, Canada and GEMINI lead investigator. "The data from the GEMINI program suggest that vedolizumab may provide people living with CD and UC an additional option for inducing and maintaining clinical remission."

In the publication, study results from GEMINI I, a placebo-controlled induction and maintenance study in patients with UC, showed that vedolizumab met primary endpoints of improvement in clinical response (reduction in the Mayo Clinic score of ≥3 points and ≥30 percent from baseline, along with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1) at six weeks and clinical remission (Mayo score of 2 or lower and no subscore higher than 1) at 52 weeks. In addition, a significantly greater proportion of patients receiving vedolizumab achieved mucosal healing (Mayo endoscopic subscore of 0 or 1) at six and 52 weeks, and glucocorticoid-free remission at 52 weeks, compared with placebo. Discussed in a separate publication, results from GEMINI II, a placebo-controlled induction and maintenance study in patients with CD, showed that vedolizumab demonstrated statistically significant improvement in the primary endpoint of clinical remission (Crohn's disease activity index [CDAI] score ≤150 points) at six weeks and at 52 weeks compared to placebo. At six weeks, no significant difference was observed in the co-primary endpoint of CDAI-100 response (≥100-point decrease in the CDAI score) between the vedolizumab and placebo groups. A significantly greater proportion of patients showed CDAI-100 response and glucocorticoid-free remission at 52 weeks.

GEMINI I and GEMINI II are part of the four-study GEMINI Studies™, studying vedolizumab in 2,700 patients in nearly 40 countries, making it the largest Phase 3 clinical trial program conducted to date simultaneously evaluating both CD and UC. Enrolled patients had failed at least one conventional therapy, including glucocorticoids, immunomodulators and/or a tumor necrosis factor-alpha (TNF-alpha) antagonist. TNF-alpha antagonist failure patients included those with inadequate response (primary non-responders), loss of response (secondary non-responders) or those who were intolerant.

"These clinical studies suggest that vedolizumab may have the potential to maintain clinical remission in the appropriate patients," said Asit Parikh, M.D., Ph.D., vice president, general medicine, Takeda. "Takeda has a strong legacy of researching and treating GI disorders globally, and vedolizumab represents our focus on and commitment to patient communities."

Takeda submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) in June, 2013, as well as a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) in March, 2013, seeking approval for vedolizumab for the treatment of adults with moderately to severely active CD and UC.

CD and UC are chronic diseases of the digestive tract. CD can involve all areas of the digestive tract, while UC typically affects the colon and rectum. CD and UC can be both painful and debilitating and patients may have bleeding, diarrhea, fatigue, weight loss and anemia, among other symptoms. Both diseases involve excess inflammation in the gut tissue that occurs when white blood cells infiltrate the gastrointestinal tract and may lead to serious complications. 

"Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis"

The publication, titled "Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis", discusses findings from GEMINI I, a Phase 3, randomized, double-blind, placebo-controlled induction and maintenance study designed to assess the efficacy and safety of vedolizumab on clinical response and remission in patients with moderately to severely active UC, in whom one prior therapy had failed. In the induction phase, the primary endpoint was improvement in clinical response at six weeks. Secondary endpoints were to determine the effect of vedolizumab induction treatment on clinical remission and mucosal healing at six weeks. The intent-to-treat (ITT) population comprised 374 patients, with an additional 521 patients receiving open-label vedolizumab. Of the 374, 225 received vedolizumab 300 mg IV and 149 received placebo on days 1 and 15. Approximately 40 percent of the ITT population had prior anti-TNF failure. At week six, 47.1 percent of patients receiving vedolizumab achieved clinical response compared to 25.5 percent of patients receiving placebo (p<0.001), 16.9 percent achieved clinical remission versus 5.4 percent receiving placebo (p=0.001), and 40.9 percent of vedolizumab-treated patients experienced mucosal healing compared to 24.8 percent of patients receiving placebo (p=0.001).

The maintenance arm of GEMINI I assessed the efficacy and safety of vedolizumab for maintaining clinical response and remission for 52 weeks in patients with moderately to severely active UC with evidence of clinical response and decrease of rectal bleeding after two 300 mg IV induction doses of vedolizumab. The primary endpoint was clinical remission at week 52, while the secondary endpoints were durable clinical response (response at both week six and 52) and durable clinical remission (remission at both week six and 52), mucosal healing at week 52, and glucocorticoid-free remission at week 52 in patients receiving glucocorticoids at week six. Of 895 patients enrolled, 373 met response criteria at six weeks (ITT population) and were randomized to receive vedolizumab 300 mg IV every four weeks (n=125) or eight weeks (n=122), or placebo (n=126) for up to 52 weeks. 41.8 percent and 44.8 percent of patients receiving vedolizumab every eight and four weeks, respectively, were in clinical remission at week 52, compared to 15.9 percent of patients who received placebo (p<0.001). 56.6 percent and 52.0 percent of patients treated with vedolizumab every eight and four weeks, respectively, achieved durable clinical response (defined by a response at both week six and week 52), compared to 23.8 percent of patients receiving placebo (p<0.001). 51.6 percent and 56.0 percent of patients treated with vedolizumab every eight and four weeks, respectively, achieved mucosal healing at week 52, compared to 19.8 percent of patients receiving placebo (p<0.001). 20.5 percent and 24.0 percent of patients treated with vedolizumab every eight and four weeks, respectively, achieved durable clinical remission at week 52, compared to 8.7 percent of patients receiving placebo (p=0.008, p=0.001, respectively). 31.4 percent and 45.2 percent of patients on oral glucocorticoids at baseline treated with vedolizumab every eight and four weeks, respectively, achieved glucocorticoid-free remission at week 52, compared to 13.9 percent of patients receiving placebo (p=0.01, p<0.001, respectively).

The safety population in GEMINI I comprised 895 patients for weeks 0-52. The most common adverse events reported in the 620-patient vedolizumab arm (≥9.0 percent) were ulcerative colitis, headache, nasopharyngitis and arthralgia. The most common adverse events reported in the 275-patient placebo arm (˃9.0 percent) were ulcerative colitis, headache, nasopharyngitis and arthralgia. No increase in rates of serious, opportunistic or enteric infections was observed with vedolizumab. One death occurred in a 66-yr-old man who received one induction dose of vedolizumab and died 14 days later from acute coronary syndrome.

"Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease"

The publication, titled "Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease", discusses findings from GEMINI II, a Phase 3, randomized, parallel-group, double-blind, placebo-controlled induction and maintenance study designed to assess the efficacy and safety of vedolizumab as a therapy for adults with moderately to severely active Crohn's disease (CD), in whom one prior therapy had failed. In the induction phase, the co-primary endpoints were clinical remission and CDAI-100 response at week six, while the secondary endpoint was mean change in serum C-reactive protein (CRP) levels from baseline to week six. The ITT population comprised 368 patients, with an additional 747 patients receiving open-label vedolizumab. Of the 368, 220 received vedolizumab 300 mg IV and 148 received placebo. Approximately 50 percent of the ITT population had prior anti-TNFalpha failure; 26 percent were primary failures. In addition, approximately 30 percent had failed at least two TNF antagonists. At week six, clinical remission was seen in 14.5 percent of patients randomized to vedolizumab versus 6.8 percent who received placebo (p=0.02). At six weeks, no significant difference was observed in CDAI-100 response between the vedolizumab and placebo groups (31.4 percent versus 25.7 percent, respectively [p=0.23]). 

The maintenance arm of GEMINI II assessed the efficacy and safety of vedolizumab for maintaining response and remission in patients with moderately to severely active CD with evidence of clinical response after two 300 mg IV induction doses of vedolizumab. Patients responding (≥70-point decrease in CDAI from baseline) at week six to induction treatment with vedolizumab were randomized to vedolizumab 300 mg IV every four weeks, every eight weeks, or placebo for up to 52 weeks. The primary endpoint was clinical remission at week 52, while the secondary endpoints were CDAI-100 response, glucocorticoid-free remission at week 52, and durable clinical remission (clinical remission at ≥80 percent of visits including the final visit) at week 52. Of the 1,115 patients who received induction treatment, 461 met response criteria at six weeks (ITT population) and were randomized to receive vedolizumab every four weeks (n=154) or eight weeks (n=154), or placebo (n=153). At week 52, remission was seen in 39.0 percent and 36.4 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 21.6 percent of the patients receiving placebo (p<0.001, p=0.004, respectively). CDAI-100 response was seen in 43.5 percent and 45.5 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 30.1 percent of patients receiving placebo at week 52 (p=0.01, p=0.005 respectively). Glucocorticoid-free remission was seen in 31.7 percent and 28.8 percent of patients taking oral glucocorticoids at baseline randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 15.9 percent of patients receiving placebo at week 52 (p=0.02, p=0.04, respectively).

The safety population in GEMINI II comprised 1,115 patients for weeks 0-52. The most common adverse events reported in the 814-patient vedolizumab arm (˃8.0 percent) were Crohn's disease exacerbation, arthralgia, pyrexia, nasopharyngitis, headache, nausea and abdominal pain. The most common adverse events reported in the 301-patient placebo arm (≥8.0 percent) were Crohn's disease exacerbation, headache, arthralgia, pyrexia, abdominal pain, nausea and nasopharyngitis. Five deaths occurred during the study period, four among patients receiving vedolizumab (one death each from Crohn's disease with sepsis, intentional overdose of prescription medication, myocarditis, and septic shock) and one in the placebo group (from bronchopneumonia).

About the GEMINI™ Studies          

Announced in early 2009, the GEMINI Studies™ is a Phase 3 program evaluating the effect of vedolizumab on clinical response and remission (along with effect on mucosal healing in UC), and long-term safety in moderately to severely active CD and UC patients who had failed at least one conventional therapy or a TNFalpha antagonist. The GEMINI program consists of four separate studies – a placebo-controlled induction and maintenance study in patients with UC (GEMINI I), a placebo-controlled induction and maintenance study in patients with CD (GEMINI II), a placebo-controlled induction study in patients with CD (GEMINI III) and an open-label long-term safety study in patients with either CD or UC (GEMINI LTS).

About Crohn's disease and ulcerative colitis

Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of inflammatory bowel disease (IBD), which is marked by inflammation in the GI tract. CD and UC can, in many patients, present in mild form, which can be well managed. CD can impact any part of the digestive tract and common symptoms may include abdominal pain, diarrhea, rectal bleeding, weight loss, and fever. UC impacts the large intestine only, which includes the colon and the rectum. The most common symptoms of UC include abdominal discomfort and blood or pus in diarrhea. There is no known cause for CD or UC, although many researchers believe that the interaction between genes, the body's immune system, and environmental factors may play a role. The aim of CD and UC treatments is to induce and maintain remission, or achieve extended periods of time when patients do not experience symptoms.

About vedolizumab

Vedolizumab, under development for the treatment of CD and UC, is a humanized monoclonal antibody that specifically antagonizes the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal cell adhesion molecule (MAdCAM-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 CD and UC. 

About Takeda Pharmaceutical Company Limited

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine. Additional information about Takeda is available through its corporate website, www.takeda.com.