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武田vedolizumab结肠炎和克罗恩病中显现疗效

  1. vedolizumab
  2. 克罗恩病
  3. 单抗
  4. 武田
  5. 结肠炎

来源:生物谷 2013-08-23 14:23

2013年8月23日讯 /生物谷BIOON/ --武田(Takeda)8月22日公布了实验性单抗药物vedolizumab 2个III期临床试验的数据,评估了vedolizumab对中至重度活动性溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD)的治疗。

2013年8月23日讯 /生物谷BIOON/ --武田(Takeda)8月22日公布了实验性单抗药物vedolizumab 2个III期临床试验的数据,评估了vedolizumab对中至重度活动性溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD)的治疗。相关数据均已发表于8月22日的《新英格兰医学杂志》(New England Journal of Medicine)。

GEMINI I是一项安慰剂对照的诱导和维持研究,在UC患者中开展,研究结果表明,与安慰剂相比,vedolizumab达到了改善临床反应(治疗6周时)和临床缓解(治疗52周时)的主要终点。此外,vedolizumab治疗组实现黏膜愈合(治疗6周和52周时)、无糖皮质激素临床缓解(52周时)的患者比例显着高于安慰剂组。

GEMINI II是一项安慰剂对照的诱导和维持研究,在CD患者中开展,研究结果表明,与安慰剂相比,vedolizumab显着改善了临床缓解(治疗6周和52周时)的主要终点,数据具有统计学显着意义。治疗6周时,vedolizumab组和安慰剂组在共同主要终点CDAI-100反应无显着差异。治疗52周时,vedolizumab治疗组实现CDAI-100反应、无糖皮质激素临床缓解的患者比例显着高于安慰剂组。

GEMINI项目包括4个III期研究,这是迄今为止在CD和UC患者中开展的最大的III期临床试验项目。

Vedolizumab是一种全人源化单克隆抗体,特异性拮抗α4β7整合素,抑制α4β7整合素对肠道黏膜细胞粘附分子MAdCAM-1的结合。MAdCAM-1选择性表达于肠胃血管和淋巴结。α4β7整合素表达于一组循环(circulating)白细胞,这些细胞已被证明在CD和UC疾病中介导炎症过程中发挥了重要作用。

武田于2013年3月向欧洲药品管理局(EMA)提交了vedolizumab的上市许可申请(MAA),并于2013年6月向FDA提交了vedolizumab的生物制品许可申请(BLA),寻求批准vedolizumab用于中度至重度活动性CD和UC患者治疗。(生物谷Bioon.com)

英文原文:Takeda's vedolizumab shows efficacy in colitis and Crohn's disease

Osaka, Japan – August 21, 2013 – 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.1,2 Chronic and debilitating diseases, CD and UC are the two most common types of inflammatory bowel disease (IBD)3,4, and affect more than four million people worldwide,5,6,7,8,9,10including approximately 1.4 million Americans and 2.2 million Europeans.11,12Vedolizumab is designed to specifically antagonize the alpha4beta7 (α4β7) 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.13,14

“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.15 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.16

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.17,18,19 Enrolled patients had failed at least one conventional therapy, including glucocorticoids, immunomodulators and/or a tumor necrosis factor-alpha (TNF-α) antagonist. TNF-α antagonist failure patients included those with inadequate response (primary non-responders), loss of response (secondary non-responders) or those who were intolerant.20,21,22

“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.23 CD can involve all areas of the digestive tract, while UC typically affects the colon and rectum.24,25CD and UC can be both painful and debilitating and patients may have bleeding, diarrhea, fatigue, weight loss and anemia, among other symptoms.26,27,28 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.29,30

“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.31 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=0.01, 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.34

“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.35 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-TNFα 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]).36

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).38

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 TNFα antagonist.39,40,41,42,43 The GEMINI program consists of four separate studies – a placebo-controlled induction and maintenance study in patients with UC (GEMINI I),44 a placebo-controlled induction and maintenance study in patients with CD (GEMINI II),45 a placebo-controlled induction study in patients with CD (GEMINI III)46 and an open-label long-term safety study in patients with either CD or UC (GEMINI LTS).47

About vedolizumab

Vedolizumab, under development for the treatment of CD and UC, is a humanized monoclonal antibody that specifically antagonizes the alpha4beta7 (α4β7) integrin, inhibiting the binding of α4β7 integrin to intestinal mucosal cell adhesion molecule (MAdCAM-1).55 MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.56 The α4β7 integrin is expressed on a subset of circulating white blood cells.57 These cells have been shown to play a role in mediating the inflammatory process in CD and UC.58,59

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