Clinical Trials

Date: 2017-02-17

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 12th Congress of European Crohn's and Colitis Organisation (ECCO)

Company: Takeda Pharmaceutical (Japan)

Product: Entyvio® (vedolizumab)

Action mechanism:

• monoclonal antibody. Vedolizumab is a gut-selective humanized monoclonal antibody available in the United States and the European Union, under the trade name Entyvio® (vedolizumab). It is designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and fibronectin, 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 UC and CD. By inhibiting alpha4beta7, vedolizumab may limit the ability of certain white blood cells to infiltrate gut tissues.
• Vedolizumab is the first and only biologic therapy to be approved in the European Union simultaneously for the treatment of adults with moderately to severely active ulcerative colitis or 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 antagonist.

Disease: moderately to severely active ulcerative colitis, Crohn's disease

Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases

Country: Australia, Belgium, Canada, Czech Republic, Germany, Hungary, Israel, Republic of Korea, Malaysia, Puerto Rico

Trial details:

• The GEMINI 1 and 2 studies are two randomized double-blind, placebo-controlled studies examining the efficacy and safety of vedolizumab for induction and maintenance in adult patients with moderately to severely active ulcerative colitis and Crohn's disease, respectively. GEMINI 1 was a multicenter, phase 3, randomized, placebo-controlled trial. As part of the eligibility criteria for GEMINI 1, patients had demonstrated, within the previous 5-year period, an inadequate response to, loss of response to, or intolerance of  at least 1 of the following therapies: corticosteroids (outside the United States only), immunosuppressives (azathioprine or mercaptopurine), and/or infliximab, as this was the only TNF antagonist approved for the treatment of ulcerative colitis at the time of enrollment. The study enrolled 464 patients without prior TNF antagonist therapy (TNF-naïve) and 367 who had failed therapy because of inadequate response, loss of response or intolerance (TNF-failure).
• GEMINI LTS is a Phase 3, ongoing, open-label extension study examining the long-term safety and efficacy of vedolizumab for the treatment of adults with moderately to severely active UC and CD. One hundred and forty six patients with Crohn’s disease were enrolled from GEMINI II and 154 patients with ulcerative colitis were enrolled from GEMINI I.
• GEMINI 1 (NCT00783718), GEMINI II (NCT00783692), GEMINI III (NCT01224171), GEMINI LTS (NCT00790933)

Latest news:

• • On February 17, 2017, Takeda announced that interim findings from the ongoing, open-label GEMINI long-term safety (LTS) study were presented during the 12th Congress of European Crohn's and Colitis Organisation (ECCO) in Barcelona. Data presented from two five-year interim analyses of effectiveness and safety in patients with moderate to severely active ulcerative colitis and Crohn’s disease indicated that long-term treatment of vedolizumab in responders was associated with long-term clinical response and remission in addition to health-related quality of life improvements for patients over a five year period. This interim analysis reports clinical effectiveness evaluated at five years. Fifty-eight patients with Crohn’s disease and 54 patients with ulcerative colitis had discontinued therapy before the data cut-off, (11 [19%] and 19 [35%] patients discontinuing respectively due to lack of benefit). Twenty-seven Crohn’s disease patients and 37 ulcerative colitis patients had not reached the five year assessment time point in the study. Sixty-one patients with Crohn’s disease and 63 patients with ulcerative colitis were evaluated in the analysis. Patients with Crohn’s disease were assessed for clinical response (decrease in Harvey–Bradshaw Index [HBI] greater than  or equal to 3 points from BL). Clinical remission was defined as HBI less than  or equal to 4. Patients with ulcerative colitis were assessed for clinical response (decrease in partial Mayo Score [PMS] of more than or equal to 2 points and greater than  or equal to 25% change from baseline [BL], with an accompanying decrease in rectal bleeding subscore of more or equal to 1 point from BL or absolute rectal bleeding subscore of  less or equal to 1 point). Clinical remission was defined as PMS of less or equal to 2 with no individual subscore >1. This interim analysis showed that for the 63 observed patients with moderate to severely active ulcerative colitis, 98% experienced clinical response, and 90% were in clinical remission after five years of continued vedolizumab treatment. For the 61 observed patients with moderate to severely active Crohn's disease, 95% experienced clinical response and 89% were in clinical remission after five years of continued vedolizumab treatment. Long-term use of vedolizumab was also associated with improvements in HRQL, which was measured by IBD Questionnaire (IBDQ) and Euro Quality of Life-5D visual analogue scale (EQ-5D VAS). The safety profile was consistent with that previously observed in a three-year interim analysis of the LTS study in patients with moderate to severely active ulcerative colitis and Crohn’s disease.
• Additional data from a post-hoc analysis of GEMINI I reported vedolizumab (n=620) was significantly more effective than placebo (n=149) at achieving sustained remission, defined as clinical remission (PMS ?2 points with no individual subscore >1 point) and rectal bleeding subscore equaling 0 at weeks 26, 38 and 52, in patients with moderate to severely active UC who achieved remission at week 14. The analysis included patients enrolled in GEMINI I, who responded to two induction doses of vedolizumab and entered 46 weeks of maintenance therapy with either placebo or vedolizumab. Maintenance treatment with vedolizumab resulted in 60% of patients sustaining clinical remission from week 14 to week 52 compared with 37% who underwent placebo washout.
• • On December 9, 2016, Takeda Pharmaceutical announced that an analysis based on pre-specified and post-hoc exploratory outcomes of GEMINI II and GEMINI III data evaluating vedolizumab therapy in patients with moderately to severely active Crohn’s disease  was published in Inflammatory Bowel Diseases. The data demonstrated higher rates of response in patients receiving vedolizumab as a first-line biologic after conventional therapy failure versus patients who had previously experienced tumor necrosis factor-alpha (TNF-?) antagonist therapy failure. Among patients who responded to vedolizumab induction at week 6, 48.9 percent of TNF-naïve and 27.7 percent of TNF-failure patients were in remission with vedolizumab at week 52 (vs 26.8 percent and 12.8 percent with placebo).
• Investigators examined data from 516 patients who were TNF-naïve and 960 patients who had failed prior TNF? antagonist therapy in the combined GEMINI II and GEMINI III study populations.1 In TNF-naïve patients who achieved remission, the treatment difference from placebo was significant at week six (12.6 percent difference; 95 percent CI: 3.7, 21.4) and week 10 (11.3 percent difference; 95 percent CI: 1.5, 21.1). For TNF-failure patients who achieved remission, the treatment difference from placebo reached significance at week 10 (11.5 percent difference; 95 percent CI: 4.5, 18.6).  There were no differences in adverse events among treatment groups in this study. In this analysis, compared to placebo, treatment with vedolizumab also showed clinical efficacy of vedolizumab maintenance therapy at week 52 irrespective of the number of prior TNF-? antagonist failed. Additionally, trends favoring vedolizumab induction were observed across all three measures  of TNF-? antagonist failure assessed in the study: inadequate response, loss of response or intolerance, and number of prior TNF-? antagonists used. As clinical response/remission rates may be diminished when switching to a second or third TNF-? antagonist, these results support evaluating a treatment switch; to a therapy with a different mode of action, such as vedolizumab.
• • On September 29, 2016,Takeda announced that two interim reports from the ongoing, open-label GEMINI long-term safety (LTS) study describing clinical data of long-term Entyvio (vedolizumab) treatment in patients with moderately to severely active ulcerative colitis  and moderately to severely active Crohn's disease have been published in the Journal of Crohn’s & Colitis. The data showed that patients with moderately to severely active UC experienced clinical and healthrelated quality of life (HRQL) improvements with continued vedolizumab treatment. For patients with moderately to severely active CD, the clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. UC and CD patients that entered the study after discontinuing prior eight-weekly maintenance dosing due to loss of clinical response, in GEMINI I and II respectively, could experience a beneficial effect with increasing dosing frequency to every four weeks. The interim reports published in the Journal of Crohn’s & Colitis represent efficacy data collected from May 22, 2009 to June 27, 2013. Outcomes of clinical response, remission and HRQL were assessed for up to 152 weeks of treatment in the efficacy population.
• A total of 894 patients with UC were enrolled in the GEMINI LTS study and constituted the safety population, and a subset of 845 patients with moderately to severely active UC constituted the efficacy population. As of June 27, 2013, 63 percent of the efficacy population (n=532/845) were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88 percent (n=120/136) were in remission after 104 weeks of exposure (96 percent [n=70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI I (n=32) before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41 percent and 28 percent, respectively, after 52 weeks, an increase from 19 percent and 6 percent, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior TNF antagonist exposure. Durable benefits on HRQL were also observed.
• A total of 1,349 patients with CD enrolled in the GEMINI LTS study and constituted the safety population. The efficacy population comprised 1,297 patients with moderately to severely active CD: 700 from GEMINI II, 372 from GEMINI III, and 225 vedolizumab-naïve patients.Among patients with response at week 6 in GEMINI II who received vedolizumab continuously, 83 percent (n=100/120) and 89 percent (n=62/70) of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks (GEMINI II) to every 4 weeks (GEMINI LTS) improved outcomes in patients who had withdrawn early from GEMINI II, with 47 percent (n=27/57) experiencing clinical response and 32 percent (n=18/57) in remission at week 52 of GEMINI LTS (up from 39 percent and 4 percent before the dose increase). Similar improvements were observed regardless of prior TNF antagonist exposure. Long-term benefits of HRQL were also observed.
• Patients who were previously exposed to vedolizumab in the GEMINI II and GEMINI III trials demonstrated a reduction in disease activity which was sustained with long-term open-label vedolizumab therapy. After an additional 100 weeks (week 152) of treatment, 74 percent (n=156/212) of all patients who completed GEMINI II were in remission including 66 percent (n=75/113) of those with prior TNF antagonist failure and 82 percent (n=69/84) of TNF antagonist naïve patients. Long-term benefits of HRQL were also observed.
• • On September 16, 2016, Takeda announced that an exploratory analysis of the GEMINI 1 data, evaluating Entyvio® (vedolizumab) therapy in patients with ulcerative colitis based on their treatment history with tumor necrosis factor (TNF) antagonists was published in Clinical Gastroenterology and Hepatology. The sub-group analysis, compared TNF-naïve with TNF-failure patients with moderately to severely active ulcerative colitis. The former had never received TNF antagonist therapy whilst those who had received and failed therapy due to inadequate response, loss of response or intolerance were in the latter group.
• Overall, the publication reported a statistically significantly greater efficacy with vedolizumab treatment compared to placebo in both subgroups of patients. Investigators examined primary and secondary outcomes data from the GEMINI 1 study, after 6 weeks and 52 weeks of vedolizumab therapy in patient sub-groups who were either TNF-naïve or failed TNF antagonist therapy. The analysis reported that vedolizumab treatment had statistically significantly greater efficacy compared to placebo in inducing and maintaining clinical response in both sub-groups of patients. Furthermore, greater treatment differences favoring vedolizumab treatment at week 6 were observed for TNF-naïve patients, compared to TNF-failure patients. There were no differences in adverse events among treatment groups in this study.
• Investigators evaluated predefined outcomes data from the GEMINI 1 clinical trial (Phase 3) of vedolizumab examining treatment with vedolizumab in patients with moderately to severely active ulcerative colitis. In the present analyses, the TNF-failure population comprised an aggregate of patients with inadequate response, loss of response, or intolerance to prior TNF antagonist treatment as pre-defined according to data captured on the case report form (CRF) at baseline (week 0). The primary outcome measure for induction therapy was a clinical response at week 6. Secondary outcome measures were clinical remission and mucosal healing at week 6. For maintenance therapy, the primary outcome was clinical remission at week 52. Efficacy outcomes in TNF-naïve and TNF-failure patient sub-groups were analyzed in terms of the absolute difference in percentages for vedolizumab and placebo and the risk ratios (RRs). The RR is a measure of treatment efficacy, adjusted for any variabilities within the patient sub-groups, with RR > 1 indicating greater efficacy with vedolizumab. Investigators found greater absolute differences between vedolizumab and placebo for TNF-naïve patients than for TNF-failure patients at week 6 and the risk ratios (RRs) were similar. Week 6 response rates with vedolizumab and placebo were 53.1% and 26.3%, respectively, in TNF-naïve patients (AD: 26.4%; 95% confidence interval [CI]: 12.4, 40.4; RR: 2.0; 95% CI: 1.3, 3.0) and 39.0% and 20.6%, respectively, in TNF-failure patients (AD: 18.1%; 95% CI: 2.8, 33.5; RR: 1.9; 95% CI: 1.1, 3.2).
• During maintenance, the absolute differences were similar and the RRs were higher for TNF-failure patients for most outcomes. Week 52 remission rates with vedolizumab and placebo were 46.9% and 19.0%, respectively, in TNF-naïve patients (AD: 28.0%; 95% CI: 14.9, 41.1; RR: 2.5; 95% CI: 1.5, 4.0) and 36.1% and 5.3%, respectively, in TNF-failure patients (AD: 29.5%; 95% CI: 12.8, 46.1; RR: 6.6; 95% CI: 1.7, 26.5).1
• • On May 19, 2015, Takeda Pharmaceuticals announced that data highlighting the efficacy and safety of vedolizumab for the treatment of adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD) were presented at the 2015 Digestive Disease Week (DDW) Annual Meeting in Washington, D.C. Twelve Takeda-sponsored presentations, including one oral presentation, were featured during the meeting May 16-19, 2015. The presentations included data from the Phase 3 pivotal studies GEMINI 1 (UC) and GEMINI 2 (CD), as well as interim data from the ongoing, open-label extension study GEMINI LTS (long-term safety). Findings from an analysis of cost per-clinical-outcome for the treatment of moderately to severely active UC with biologic therapy were highlighted during an oral presentation on Saturday, May 16, 2015, as part of a larger session titled "Bending the Cost Curve in Gastroenterology": Astract # 2160225: Cost per clinical outcomes with biologics for the treatment of moderately to severely active ulcerative colitis (Jansen, Mody, Patel, et al). In addition, several Takeda-sponsored abstracts highlighting safety, efficacy, and cost-effectiveness information for vedolizumab were also presented as poster sessions.
• • On February 20, 2015,Takeda Pharmaceutical announced the presentation of data further demonstrating the efficacy and safety of vedolizumab for the treatment of adults with moderately to severely active ulcerative colitis and Crohn's disease. Findings from the Phase 3 pivotal GEMINI 1 (ulcerative colitis) and GEMINI 2 (Crohn's disease) studies, as well as interim data from the ongoing, open-label extension study GEMINI LTS (long-term safety) were presented as oral digital presentations and poster presentations during the 10th Congress of European Crohn's and Colitis Organisation (ECCO) in Barcelona, Spain. A total of 18 Takeda-sponsored abstracts were accepted for presentation at the meeting.
• The GEMINI 1 and 2 studies are two randomized double-blind, placebo-controlled induction and maintenance studies examining the efficacy and safety of vedolizumab for induction and maintenance in adult patients with moderately to severely active UC and CD, respectively. GEMINI LTS is a Phase 3, ongoing, open-label extension study examining the long-term safety and efficacy of vedolizumab for the treatment of adults with moderately to severely active UC and CD. Key data presentations include:
• Efficacy and safety of retreatment with vedolizumab in patients with ulcerative colitis (oral presentation) (Sands, Shafran, Farraye, et al.) Background: The effects of vedolizumab retreatment after up to one year of drug holiday in UC patients who, after initial response, were re-randomized to placebo or lost response during GEMINI 1, were evaluated using an interim analysis (22 May 2009 – 27 June 2013) of data from GEMINI LTS. Key Finding(s): The analysis suggested that for patients who responded to vedolizumab induction treatment and stopped treatment for up to one year, retreatment with vedolizumab in GEMINI LTS resulted in a good efficacy and safety profile. Efficacy and safety of retreatment with vedolizumab in patients with Crohn's disease (Sands, Shafran, Farraye, et al.) Background: An interim analysis (22 May 2009 – 27 June 2013) examined the effects of vedolizumab retreatment in GEMINI 2 patients who enrolled in GEMINI LTS after a drug holiday of up to one year. Key Finding(s): The analysis indicated that for patients who responded to vedolizumab induction treatment and stopped treatment for up to one year, retreatment with vedolizumab in GEMINI LTS resulted in a good efficacy and safety profile. Deep remission as a predictor of clinical outcomes in vedolizumab-treated patients with ulcerative colitis (Sandborn, Colombel, Panaccione, et al.) Background: Deep remission (combination of endoscopic and patient-reported outcomes) is an emerging treatment goal in ulcerative colitis. Post-hoc analyses of GEMINI 1 study data investigated whether deep remission is a predictor of clinical outcomes and health-related quality of life (HRQoL) in patients with UC. Key Finding(s): Deep remission at week 6 was a consistent predictor of positive outcomes at week 52, and vedolizumab-treated patients were nearly 3-times as likely to be in deep remission at week 52 compared with placebo-treated patients. Patients in deep remission at week 6 or 52 had better clinical and HRQoL outcomes at week 52 than those who were not in deep remission. Deep clinical remission in patients with ulcerative colitis: evaluating the effects of vedolizumab on various combinations of endoscopic and patient-reported outcomes (Sandborn, Colombel, Panaccione, et al.) Background: Post-hoc analyses of GEMINI 1 study data evaluated the impact of vedolizumab on deep remission using various combinations of endoscopic outcomes and patient-reported outcomes. Key Finding(s): Vedolizumab led to statistically significant and clinically meaningful improvements at week 6 for three of four deep remission endpoints and at week 52 for all four endpoints. Clinical response and remission with vedolizumab across a range of baseline fecal calprotectin levels in ulcerative colitis: results from GEMINI 1 (oral presentation) (Reinisch, Lewis, Dassopoulos, et al.) Background: It is thought that fecal calprotectin (fCal) concentration reflects intestinal inflammation. A correlation between fCal concentrations and response to vedolizumab was evaluated using GEMINI 1 measurements of fCal concentrations. Key Finding(s): At week 6, response and remission rates were numerically higher with vedolizumab than placebo regardless of baseline fCal, and a 69 percent decrease in geometric mean of fCal was observed for vedolizumab-treated patients, compared to a 32 percent decrease for placebo-treated patients. Relationship between vedolizumab pharmacokinetics and endoscopic outcomes in patients with ulcerative colitis (oral presentation) (Rosario, Abhyankar, Sankoh, et al.) Background: Mucosal healing in ulcerative colitis has been associated with higher serum levels of tumor necrosis factor antagonists. Investigators studied the pharmacokinetics of vedolizumab (300mg) in relation to endoscopic outcomes. Key Finding(s): In GEMINI 1, at week 6, mucosal healing was more common and endoscopic subscores were lower in patients with higher measured vedolizumab trough concentration values than in those with lower values. Cost per clinical outcomes with biologics for the treatment of moderately to severely active ulcerative colitis (Jansen, Mody, Ursan, et al.) Background: Cost per clinical outcomes of vedolizumab was compared with other licensed biologics over a one year treatment period for anti-tumor necrosis factor (TNF) naive and anti-TNF experienced patients with moderate-to-severe UC from a United Kingdom perspective. Key Finding(s): This analysis indicated that vedolizumab had a lower number-needed-to-treat and cost per patient for sustained response/remission, potentially providing better clinical and economic value than other biologics approved for the treatment of patients with moderate-to-severe UC.

Is general: Yes