Vedolizumab shows promise in Crohn’s, ulcerative colitis

The humanized monoclonal antibody vedolizumab is more effective than placebo for induction and maintenance therapy in both ulcerative colitis and Crohn’s disease, according to two separate randomized, controlled phase III studies: GEMINI 1 and GEMINI 2.

The findings from the double-blind, multinational studies were published in the Aug. 22 issue of the New England Journal of Medicine.

GEMINI 1

In GEMINI 1, the clinical response rates at 6 weeks in 374 patients (cohort 1) with active ulcerative colitis who were randomized to receive either induction therapy with vedolizumab or placebo were 47.1% and 25.5%, respectively (P less than .001). In 521 patients (cohort 2) who received open-label vedolizumab, the clinical response rate at 6 weeks was 44.3%.

In a trial of maintenance therapy, those patients from both cohorts who responded to vedolizumab at week 6 were then randomized to receive either vedolizumab or placebo every 4 or 8 weeks for up to 52 weeks. The clinical remission rates at 52 weeks were 44.8% in the group that received vedolizumab every 4 weeks, 41.8% in the group that received it every 8 weeks, and 15.9% among the patients who were switched to placebo, Dr. Brian G. Feagan of the University of Western Ontario, London, and his colleagues reported on behalf of the GEMINI 1 Study Group.

Patients in the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. Clinical response was defined as a reduction of at least 3 points in the 0- to 12-point Mayo Clinic score and a decrease of at least 30% from the baseline score, along with a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The secondary outcome of clinical remission was defined as a Mayo Clinic score of 2 or less, with no subscore higher than 1, along with mucosal healing, defined by an endoscopic subscore of 0 or 1, the investigators said (N. Engl. J. Med. 2013;369:699-710).

The GEMINI 1 researchers noted that "all prespecified, primary and secondary outcomes in the trial of induction and maintenance therapy were superior in vedolizumab-treated patients versus those who received placebo," and added that longitudinal assessment of a number of factors, such as Mayo Clinic scores and use or dose of glucocorticoids, provided further evidence of a treatment benefit.

Furthermore, disease had been refractory to other treatments in many patients, they noted.

While the study was not designed to identify the time of the maximal effect of treatment as induction therapy, or a minimally effective dose regimen, it appears that treatment every 8 weeks may be an acceptable starting regimen – with dose intensification if needed, they said. "Vedolizumab is effective as both induction and maintenance therapy for patients with moderately to severely active ulcerative colitis," they concluded.

GEMINI 2

In GEMINI 2, the clinical remission rates at 6 weeks in 368 patients with active Crohn’s disease who were randomized to receive either induction therapy with vedolizumab or placebo were 14.5% and 6.8%, respectively (P = .02), and a total of 31.4% and 25.7% of patients, respectively (P = .023), had a Crohn’s Disease Activity Index-100 (CDAI-100) response, defined as a decrease in the CDAI score of at least 100 points. Of 747 patients who received open-label vedolizumab, 17.7% had a clinical remission and 34.4% had a CDAI-100 response at 6 weeks.

Those patients who responded to vedolizumab in the induction phase were randomly assigned to receive either placebo or maintenance treatment every 4 or 8 weeks until week 52. The clinical remission rates at 52 weeks were 36.4% in the group that received the drug every 4 weeks, 39.0% in the group receiving it every 8 weeks, and 21.6% in the placebo group, Dr. William J. Sandborn of the University of California, San Diego, La Jolla, and his colleagues reported on behalf of the GEMINI 2 Study Group (N. Engl. J. Med. 2013; 369:711-21).

As in GEMINI 1, patients in GEMINI 2 who were assigned to the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. In GEMINI 2, clinical remission was defined as a CDAI score of 150 or less.

In GEMINI 1, the frequency of adverse events was similar in both the treatment and placebo groups, whereas in GEMINI 2, vedolizumab, compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%), the investigators said.

Patients in both GEMINI 1 and 2 were aged 18-80 years who were enrolled between 2008 and 2012 through more than 200 participating medical centers in more than 30 countries.

The findings are important because existing medical therapies for ulcerative colitis and Crohn’s disease have significant limitations, including toxic effects, and new treatment strategies are needed, the investigators said.

The GEMINI 2 investigators noted that patients with moderately to severely active Crohn’s disease, in whom conventional therapy failed, were more likely than those receiving placebo to experience remission at 6 weeks. They were not more likely to have a CDAI-100 response, however.

While the modest effect of treatment on induction of clinical remission, as well as the nonsignificant effect on the CDAI-100, require consideration, and while questions remain about which specific patients with Crohn’s disease may derive the most benefit from vedolizumab and about potential synergistic effects of combining vedolizumab with immunosuppressive agents, the findings nonetheless suggest a role for vedolizumab in Crohn’s disease, they noted.

"In an analysis of patients who had a response to induction therapy with vedolizumab, the rates of clinical remission, CDAI-100 response, and glucocorticoid-free remission at week 52 were higher among patients receiving vedolizumab every 8 weeks or every 4 weeks than among patients who were switched to placebo," they said.

GEMINI 1 and GEMINI 2 were funded by Millennium Pharmaceuticals. The authors disclosed multiple potential conflicts of interest; the details are available with the full text of the articles at NEJM.org.

The humanized monoclonal antibody vedolizumab is more effective than placebo for induction and maintenance therapy in both ulcerative colitis and Crohn’s disease, according to two separate randomized, controlled phase III studies: GEMINI 1 and GEMINI 2.

The findings from the double-blind, multinational studies were published in the Aug. 22 issue of the New England Journal of Medicine.

GEMINI 1

In GEMINI 1, the clinical response rates at 6 weeks in 374 patients (cohort 1) with active ulcerative colitis who were randomized to receive either induction therapy with vedolizumab or placebo were 47.1% and 25.5%, respectively (P less than .001). In 521 patients (cohort 2) who received open-label vedolizumab, the clinical response rate at 6 weeks was 44.3%.

In a trial of maintenance therapy, those patients from both cohorts who responded to vedolizumab at week 6 were then randomized to receive either vedolizumab or placebo every 4 or 8 weeks for up to 52 weeks. The clinical remission rates at 52 weeks were 44.8% in the group that received vedolizumab every 4 weeks, 41.8% in the group that received it every 8 weeks, and 15.9% among the patients who were switched to placebo, Dr. Brian G. Feagan of the University of Western Ontario, London, and his colleagues reported on behalf of the GEMINI 1 Study Group.

Patients in the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. Clinical response was defined as a reduction of at least 3 points in the 0- to 12-point Mayo Clinic score and a decrease of at least 30% from the baseline score, along with a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The secondary outcome of clinical remission was defined as a Mayo Clinic score of 2 or less, with no subscore higher than 1, along with mucosal healing, defined by an endoscopic subscore of 0 or 1, the investigators said (N. Engl. J. Med. 2013;369:699-710).

The GEMINI 1 researchers noted that "all prespecified, primary and secondary outcomes in the trial of induction and maintenance therapy were superior in vedolizumab-treated patients versus those who received placebo," and added that longitudinal assessment of a number of factors, such as Mayo Clinic scores and use or dose of glucocorticoids, provided further evidence of a treatment benefit.

Furthermore, disease had been refractory to other treatments in many patients, they noted.

While the study was not designed to identify the time of the maximal effect of treatment as induction therapy, or a minimally effective dose regimen, it appears that treatment every 8 weeks may be an acceptable starting regimen – with dose intensification if needed, they said. "Vedolizumab is effective as both induction and maintenance therapy for patients with moderately to severely active ulcerative colitis," they concluded.

GEMINI 2

In GEMINI 2, the clinical remission rates at 6 weeks in 368 patients with active Crohn’s disease who were randomized to receive either induction therapy with vedolizumab or placebo were 14.5% and 6.8%, respectively (P = .02), and a total of 31.4% and 25.7% of patients, respectively (P = .023), had a Crohn’s Disease Activity Index-100 (CDAI-100) response, defined as a decrease in the CDAI score of at least 100 points. Of 747 patients who received open-label vedolizumab, 17.7% had a clinical remission and 34.4% had a CDAI-100 response at 6 weeks.

Those patients who responded to vedolizumab in the induction phase were randomly assigned to receive either placebo or maintenance treatment every 4 or 8 weeks until week 52. The clinical remission rates at 52 weeks were 36.4% in the group that received the drug every 4 weeks, 39.0% in the group receiving it every 8 weeks, and 21.6% in the placebo group, Dr. William J. Sandborn of the University of California, San Diego, La Jolla, and his colleagues reported on behalf of the GEMINI 2 Study Group (N. Engl. J. Med. 2013; 369:711-21).

As in GEMINI 1, patients in GEMINI 2 who were assigned to the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. In GEMINI 2, clinical remission was defined as a CDAI score of 150 or less.

In GEMINI 1, the frequency of adverse events was similar in both the treatment and placebo groups, whereas in GEMINI 2, vedolizumab, compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%), the investigators said.

Patients in both GEMINI 1 and 2 were aged 18-80 years who were enrolled between 2008 and 2012 through more than 200 participating medical centers in more than 30 countries.

The findings are important because existing medical therapies for ulcerative colitis and Crohn’s disease have significant limitations, including toxic effects, and new treatment strategies are needed, the investigators said.

The GEMINI 2 investigators noted that patients with moderately to severely active Crohn’s disease, in whom conventional therapy failed, were more likely than those receiving placebo to experience remission at 6 weeks. They were not more likely to have a CDAI-100 response, however.

While the modest effect of treatment on induction of clinical remission, as well as the nonsignificant effect on the CDAI-100, require consideration, and while questions remain about which specific patients with Crohn’s disease may derive the most benefit from vedolizumab and about potential synergistic effects of combining vedolizumab with immunosuppressive agents, the findings nonetheless suggest a role for vedolizumab in Crohn’s disease, they noted.

"In an analysis of patients who had a response to induction therapy with vedolizumab, the rates of clinical remission, CDAI-100 response, and glucocorticoid-free remission at week 52 were higher among patients receiving vedolizumab every 8 weeks or every 4 weeks than among patients who were switched to placebo," they said.

GEMINI 1 and GEMINI 2 were funded by Millennium Pharmaceuticals. The authors disclosed multiple potential conflicts of interest; the details are available with the full text of the articles at NEJM.org.

The humanized monoclonal antibody vedolizumab is more effective than placebo for induction and maintenance therapy in both ulcerative colitis and Crohn’s disease, according to two separate randomized, controlled phase III studies: GEMINI 1 and GEMINI 2.

The findings from the double-blind, multinational studies were published in the Aug. 22 issue of the New England Journal of Medicine.

GEMINI 1

In GEMINI 1, the clinical response rates at 6 weeks in 374 patients (cohort 1) with active ulcerative colitis who were randomized to receive either induction therapy with vedolizumab or placebo were 47.1% and 25.5%, respectively (P less than .001). In 521 patients (cohort 2) who received open-label vedolizumab, the clinical response rate at 6 weeks was 44.3%.

In a trial of maintenance therapy, those patients from both cohorts who responded to vedolizumab at week 6 were then randomized to receive either vedolizumab or placebo every 4 or 8 weeks for up to 52 weeks. The clinical remission rates at 52 weeks were 44.8% in the group that received vedolizumab every 4 weeks, 41.8% in the group that received it every 8 weeks, and 15.9% among the patients who were switched to placebo, Dr. Brian G. Feagan of the University of Western Ontario, London, and his colleagues reported on behalf of the GEMINI 1 Study Group.

Patients in the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. Clinical response was defined as a reduction of at least 3 points in the 0- to 12-point Mayo Clinic score and a decrease of at least 30% from the baseline score, along with a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The secondary outcome of clinical remission was defined as a Mayo Clinic score of 2 or less, with no subscore higher than 1, along with mucosal healing, defined by an endoscopic subscore of 0 or 1, the investigators said (N. Engl. J. Med. 2013;369:699-710).

The GEMINI 1 researchers noted that "all prespecified, primary and secondary outcomes in the trial of induction and maintenance therapy were superior in vedolizumab-treated patients versus those who received placebo," and added that longitudinal assessment of a number of factors, such as Mayo Clinic scores and use or dose of glucocorticoids, provided further evidence of a treatment benefit.

Furthermore, disease had been refractory to other treatments in many patients, they noted.

While the study was not designed to identify the time of the maximal effect of treatment as induction therapy, or a minimally effective dose regimen, it appears that treatment every 8 weeks may be an acceptable starting regimen – with dose intensification if needed, they said. "Vedolizumab is effective as both induction and maintenance therapy for patients with moderately to severely active ulcerative colitis," they concluded.

GEMINI 2

In GEMINI 2, the clinical remission rates at 6 weeks in 368 patients with active Crohn’s disease who were randomized to receive either induction therapy with vedolizumab or placebo were 14.5% and 6.8%, respectively (P = .02), and a total of 31.4% and 25.7% of patients, respectively (P = .023), had a Crohn’s Disease Activity Index-100 (CDAI-100) response, defined as a decrease in the CDAI score of at least 100 points. Of 747 patients who received open-label vedolizumab, 17.7% had a clinical remission and 34.4% had a CDAI-100 response at 6 weeks.

Those patients who responded to vedolizumab in the induction phase were randomly assigned to receive either placebo or maintenance treatment every 4 or 8 weeks until week 52. The clinical remission rates at 52 weeks were 36.4% in the group that received the drug every 4 weeks, 39.0% in the group receiving it every 8 weeks, and 21.6% in the placebo group, Dr. William J. Sandborn of the University of California, San Diego, La Jolla, and his colleagues reported on behalf of the GEMINI 2 Study Group (N. Engl. J. Med. 2013; 369:711-21).

As in GEMINI 1, patients in GEMINI 2 who were assigned to the vedolizumab groups were treated with 300 mg IV at weeks 0 and 2. In GEMINI 2, clinical remission was defined as a CDAI score of 150 or less.

In GEMINI 1, the frequency of adverse events was similar in both the treatment and placebo groups, whereas in GEMINI 2, vedolizumab, compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%), the investigators said.

Patients in both GEMINI 1 and 2 were aged 18-80 years who were enrolled between 2008 and 2012 through more than 200 participating medical centers in more than 30 countries.

The findings are important because existing medical therapies for ulcerative colitis and Crohn’s disease have significant limitations, including toxic effects, and new treatment strategies are needed, the investigators said.

The GEMINI 2 investigators noted that patients with moderately to severely active Crohn’s disease, in whom conventional therapy failed, were more likely than those receiving placebo to experience remission at 6 weeks. They were not more likely to have a CDAI-100 response, however.

While the modest effect of treatment on induction of clinical remission, as well as the nonsignificant effect on the CDAI-100, require consideration, and while questions remain about which specific patients with Crohn’s disease may derive the most benefit from vedolizumab and about potential synergistic effects of combining vedolizumab with immunosuppressive agents, the findings nonetheless suggest a role for vedolizumab in Crohn’s disease, they noted.

"In an analysis of patients who had a response to induction therapy with vedolizumab, the rates of clinical remission, CDAI-100 response, and glucocorticoid-free remission at week 52 were higher among patients receiving vedolizumab every 8 weeks or every 4 weeks than among patients who were switched to placebo," they said.

GEMINI 1 and GEMINI 2 were funded by Millennium Pharmaceuticals. The authors disclosed multiple potential conflicts of interest; the details are available with the full text of the articles at NEJM.org.