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Vedolizumab for ulcerative colitis and Crohn’s disease: results and implications of GEMINI studies
Vedolizumab (VDZ) is a selective antibody against α4β7-integrin, which targets leukocyte trafficking in the gastrointestinal tract. The GEMINI studies are Phase 3, randomized, placebo-controlled trials to assess the efficacy of VDZ in induction and maintenance of moderately to severely active ulcerative colitis (GEMINI 1) and Crohn’s disease (GEMINI 2). Included in these studies are patients who have failed TNF-α antagonist therapy. GEMINI 1 showed that VDZ is an effective agent in induction and maintenance of ulcerative colitis. GEMINI 2 met one of two primary end points in the induction phase showing that VDZ is more likely to induce clinical remission compared with placebo. VDZ is an effective agent in the maintenance of Crohn’s disease. These studies pave the way to a new class of medications for treatment of inflammatory bowel disease.
Mindy CW Lam1 & Brian Bressler*,1 Division of Gastroenterology, 770–1190 Hornby Street, Vancouver, BC, V6Z 2K5, Canada *Author for correspondence: Tel.: +1 604 688 6332 Fax: +1 604 689 2004 brian_bressler@ hotmail.com 1
Keywords: α4β7-integrin • CD • Crohn’s disease • GEMINI • UC • ulcerative colitis • VDZ • vedolizumab
Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory condition of the bowel affecting approximately 1.4 million people in the US with variable ranges depending on geographic distribution. The incidence of UC ranges is 19.2 per 100,000 person-years in North America. The incidence of CD is 20.2 per 100,000 personyears in North America. The prevalence of UC is 249 per 100,000 persons and CD is 319 per 100,000 persons in North America [1] . The pathophysiology of inflammatory bowel disease (IBD) is not completely understood; however, most believes this is a process from dysregulated immune response. There is a genetic predisposition to IBD with over 160 single nucleotide polymorphisms (SNPs) mapped to be associated with the disease by the genome-wide association study [2,3] . However, most speculate that UC is a consequence of interactions between genetic, immunologic and environmental factors (such as smoking or microbiome). Treatment for UC and CD are similar, mainly aimed to reduce the inflammatory
10.2217/IMT.14.66 © 2014 Future Medicine Ltd
state by suppressing the adaptive immune system or more recently, by blocking leukocyte trafficking. Although there are regional variations in practice in terms of a ‘step-up’ or ‘top-down’ approach, the medical therapies available for either UC or CD are relatively the same. Topical anti-inflammatories, such as 5-ASA, are mainly used as induction and maintenance therapy for mild-tomoderate UC. Immunosuppressants, such as methotrexate, azathioprine or mercaptopurine are used as maintenance therapy for both CD and UC (excluding methotrexate). Biologics refer to recombinant antibodies that block cytokines or adhesion molecules that have been found to play an important role in controlling the inflammatory activity of IBD. TNF-α antagonists, such as infliximab, adalimumab, certulizumab and golimumab, have been shown to be effective for both induction and maintenance of UC (excluding certulizumab) and CD (excluding golimumab) [4–9] . Although TNF-α antagonists have dramatically changed the care of patients with IBD, there remains a
Immunotherapy (2014) 6(9), 963–971
part of
ISSN 1750-743X
963
Clinical Trial Report Lam & Bressler significant void for a safe and effective agent if patients fail anti-TNF-α therapy. Introduction to the trial GEMINI is a Phase 3, randomized, placebo-controlled, parallel trial to assess the efficacy of vedolizumab (VDZ), a α4β7-integrin antagonist, in induction and maintenance of moderately to severely active UC (GEMINI 1) [10] and CD (GEMINI 2) [11] . Patients were recruited in over 200 centers across more than 30 countries between 2008–2012. Background & rationale Inflammation is a highly regulated process involving cytokines and adhesion molecules to signal lymphocytes to area of local insult. While TNF-α antagonists hamper lymphocyte maturation, newer drug therapies are aimed at targeting the other steps in the inflammatory process, such as other cytokines (secukinumab, vidofludimus), lymphoid differentiation (ustekinumab) and leukocyte trafficking (VDZ, natalizumab). The process of lymphocyte trafficking involves lymphocyte capture, rolling and activation, arrest, adhesion, intravascular crawling and trans migration. Each of these steps is highly regulated with specific adhesion molecules. α4β7-integrin is expressed on lymphocytes that are specific for the gastro intestinal tract. The interaction of α4β7-integrin and MAdCAM-1 on endothelial cells are responsible for the arrest-phase of leukocyte trafficking [12] . In vitro assays of human peripheral blood lymphocytes found that VDZ induces internalization of α4β7-integrin and is rapidly re-expressed and functional after VDZ withdrawal. These assays also demonstrated that there were no adverse effects of VDZ including cytotoxicity, lymphocyte activation and function of memory or regulatory T cells [13] . Natalizumab is a monoclonal antibody against α4, thereby neutralizing both α4β7- and α4β1-integrins. Because of its non-selective nature, natalizumab affects lymphocyte migration to both the gut and the brain. Natalizumab has shown to be effective in treatment of relapsing-remitting multiple sclerosis (MS), likely via inhibition of lymphocyte migration to the brain [14,15] . As well, natalizumab has been shown to be beneficial in the induction and maintenance of CD [16] . However, natalizumab is associated with progressive multifocal leukoencephalopathy (PML) in both MS and CD patients, presumably due to inhibition of leukocyte trafficking to CNS, thereby reducing CNS immune surveillance [17–19] . PML is a rare demyelinating disease of the CNS caused by reactivation of polyomavirus JC (JC virus). It is a disabling disease with high mortality. There have been 398 cases of reported PML
964
Immunotherapy (2014) 6(9)
in all patients treated with natalizumab world wide as of August 2013 [20,21] . VDZ is a humanized G1 monoclonal antibody against the α4β7-integrin heterodimer. Due to the selective antagonism of the α4β7-integrin hetero dimer, VDZ is not expected to have the same risk of PML compared with natalizumab. Design GEMINI 1 inclusion criteria included adult patients with active UC, defined by Mayo Clinical score [22] ≥6 and sigmoidoscopy subscore of ≥2, and ≥15cm of disease from anal verge. GEMINI 2 inclusion criteria selects for adult patients with active CD, defined by CD for at least 3 months with Crohn’s disease activity index (CDAI) [23] of 220–450, and either CRP > 2.87 mg/l, colonoscopic findings ≥3 large ulcers or ≥10 aphthous ulcers or fecal calprotectin >250 μg/g with evidence of ulcers on imaging. GEMINI 1 and 2 limited enrollment with prior TNF-α antagonist failure to 50%. Both trials excluded patients previously exposed to natalizumab, VDZ, efalizumab and rituximab. Patients on concomitant prednisone (or equivalent dose of less than or equal to 30 mg daily), stable immunosuppressants and mesalamine were included in both studies. Glucocorticoids were tapered in patients who had response at week 6 according to a prespecified regimen. Immunosuppressants were maintained at stable dose except for the US sites, where these agents were discontinued after VDZ induction period. Both studies had two cohorts, cohort 1 was randomized for induction trial, while cohort 2 received open-labeled induction and was randomized for maintenance trial. Cohort 1 was randomized 3 to 2 into VDZ 300 mg or placebo respectively at week 0 and week 2, and cohort 2 received open-labeled VDZ 300 mg at week 0 and week 2. Response to therapy was assessed at week 6. Responders from the treatment arm in both cohorts were randomized to VDZ 300 mg every 8 weeks, VDZ 300 mg every 4 weeks or placebo. Nonresponders from the treatment arm received VDZ every 4 weeks. Placebo arm from the induction trial received placebo during the maintenance trial. GEMINI 1 enrolled 374 patients into cohort 1 and 521 patients into cohort 2 from 211 centers in 34 countries. The primary end point in the induction trial was clinical response at week 6, defined by reduction in Mayo Clinical score of at least 3 points and decrease of at least 30% from the baseline score, with decrease of at least 1 point from the rectal bleeding subscale or absolute rectal bleeding score of 0 or 1. The secondary end points in the induction trial were clinical remission at week 6 (defined by Mayo Clinical score of 2 or lower and no subscore higher than 1) and mucosal
future science group
Vedolizumab for ulcerative colitis & Crohn’s disease: results & implications of GEMINI studies
healing (defined by an endoscopic subscore of 0 or 1). The primary end point in the maintenance trial was clinical remission at week 52. The secondary end point in the maintenance trial was durable clinical response, durable clinical remission, mucosal healing and glucocorticoid-free remission at week 52 in patients receiving glucocorticoid at baseline. Durable response or remission was defined as response or remission at both weeks 6 and 52. GEMINI 2 enrolled 368 patients into cohort 1 and 747 patients into cohort 2 from 285 centers in 39 countries. The two co-primary end points in the induction trial were clinical remission (defined a CDAI score of less than or equal to 150) and CDAI-100 response at week 6 (defined as a reduction of CDAI score by at least 100 points). The secondary end point in the induction trial was change in CRP from baseline. The primary end point in the maintenance trial was clinical remission at week 52. The secondary end points in the maintenance trial were CDAI-100 response, glucocorticoid-free remission and durable clinical remission at week 52. Durable remission was defined as clinical remission in at least 80% of study visits including the final visit. Results Patients enrolled in the GEMINI trials and randomized were similar in their baseline characteristics. In GEMINI 1, the average Mayo Clinic score in placebo group was 8.6 ± 1.7 with average duration of disease at 7.1 ± 7.2 years. The average Mayo Clinic score in the combined treatment cohorts was 8.6 ± 1.8 with average duration of disease at 6.8 ± 6.2 years. 33.6% in the placebo group and 37.7% in the combined treatment cohorts had pancolitis. 38.9% were on concomitant glucocorticoids, 12.1% on immunosuppressive agents, and 17.4% were on glucocorticoids and immuno suppressive agents in the placebo group. Approximately 36.7% were on concomitant glucocorticoids, 18.9% on immunosuppressive agents and 16.5% were on glucocorticoids and immunosuppressive agents in the combined treatment cohorts. A total of 49.0 and 48.0% had received prior TNF-α antagonist in the placebo group and combined cohorts, respectively, and of those, 46.0 and 48.4% were primary nonresponders, respectively. In GEMINI 2, the average CDAI score was 325 ± 78 in the placebo group with average duration of disease at 8.2 ± 7.8 years. The average CDAI score was 323 ± 68 in the combined treatment cohorts with average duration of disease at 9.2 ± 7.8 years. Approximately 14.2% had ileal disease only and 56.8% had ileum and colonic disease in the placebo group. Approximately 16.5% had ileal disease only and 55.2% had ileum and colonic disease in the combined treatment cohorts.
future science group
Clinical Trial Report
Approximately 23.0% were current smoker in the placebo group and 27.3% in the combined treatment cohorts. Approximately 30.4% were on concomitant glucocorticoids, 16.9% on immunosuppressive agents and 17.6% were on glucocorticoids and immuno suppressive agents in the placebo group. Approximately 34.7% were on concomitant glucocorticoids, 16.1% on immunosuppressive agents and 16.9% on glucocorticoids and immunosuppressive agents in the combined treatment cohorts. Approximately 48.6 and 63.8% had received prior TNF-α antagonist in the placebo group and combined cohorts, respectively, and of those, 58.6 and 48.5% were primary nonresponders, respectively. GEMINI 1 achieved statistically significant primary and secondary end points in the induction trial by week 6 (Figure 1) . There was clinical response for 25.5% of placebo group and 47.1% of VDZ treatment group (p
Vedolizumab for ulcerative colitis and Crohn’s disease: results and implications of GEMINI studies
Vedolizumab (VDZ) is a selective antibody against α4β7-integrin, which targets leukocyte trafficking in the gastrointestinal tract. The GEMINI studies are Phase 3, randomized, placebo-controlled trials to assess the efficacy of VDZ in induction and maintenance of moderately to severely active ulcerative colitis (GEMINI 1) and Crohn’s disease (GEMINI 2). Included in these studies are patients who have failed TNF-α antagonist therapy. GEMINI 1 showed that VDZ is an effective agent in induction and maintenance of ulcerative colitis. GEMINI 2 met one of two primary end points in the induction phase showing that VDZ is more likely to induce clinical remission compared with placebo. VDZ is an effective agent in the maintenance of Crohn’s disease. These studies pave the way to a new class of medications for treatment of inflammatory bowel disease.
Mindy CW Lam1 & Brian Bressler*,1 Division of Gastroenterology, 770–1190 Hornby Street, Vancouver, BC, V6Z 2K5, Canada *Author for correspondence: Tel.: +1 604 688 6332 Fax: +1 604 689 2004 brian_bressler@ hotmail.com 1
Keywords: α4β7-integrin • CD • Crohn’s disease • GEMINI • UC • ulcerative colitis • VDZ • vedolizumab
Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory condition of the bowel affecting approximately 1.4 million people in the US with variable ranges depending on geographic distribution. The incidence of UC ranges is 19.2 per 100,000 person-years in North America. The incidence of CD is 20.2 per 100,000 personyears in North America. The prevalence of UC is 249 per 100,000 persons and CD is 319 per 100,000 persons in North America [1] . The pathophysiology of inflammatory bowel disease (IBD) is not completely understood; however, most believes this is a process from dysregulated immune response. There is a genetic predisposition to IBD with over 160 single nucleotide polymorphisms (SNPs) mapped to be associated with the disease by the genome-wide association study [2,3] . However, most speculate that UC is a consequence of interactions between genetic, immunologic and environmental factors (such as smoking or microbiome). Treatment for UC and CD are similar, mainly aimed to reduce the inflammatory
10.2217/IMT.14.66 © 2014 Future Medicine Ltd
state by suppressing the adaptive immune system or more recently, by blocking leukocyte trafficking. Although there are regional variations in practice in terms of a ‘step-up’ or ‘top-down’ approach, the medical therapies available for either UC or CD are relatively the same. Topical anti-inflammatories, such as 5-ASA, are mainly used as induction and maintenance therapy for mild-tomoderate UC. Immunosuppressants, such as methotrexate, azathioprine or mercaptopurine are used as maintenance therapy for both CD and UC (excluding methotrexate). Biologics refer to recombinant antibodies that block cytokines or adhesion molecules that have been found to play an important role in controlling the inflammatory activity of IBD. TNF-α antagonists, such as infliximab, adalimumab, certulizumab and golimumab, have been shown to be effective for both induction and maintenance of UC (excluding certulizumab) and CD (excluding golimumab) [4–9] . Although TNF-α antagonists have dramatically changed the care of patients with IBD, there remains a
Immunotherapy (2014) 6(9), 963–971
part of
ISSN 1750-743X
963
Clinical Trial Report Lam & Bressler significant void for a safe and effective agent if patients fail anti-TNF-α therapy. Introduction to the trial GEMINI is a Phase 3, randomized, placebo-controlled, parallel trial to assess the efficacy of vedolizumab (VDZ), a α4β7-integrin antagonist, in induction and maintenance of moderately to severely active UC (GEMINI 1) [10] and CD (GEMINI 2) [11] . Patients were recruited in over 200 centers across more than 30 countries between 2008–2012. Background & rationale Inflammation is a highly regulated process involving cytokines and adhesion molecules to signal lymphocytes to area of local insult. While TNF-α antagonists hamper lymphocyte maturation, newer drug therapies are aimed at targeting the other steps in the inflammatory process, such as other cytokines (secukinumab, vidofludimus), lymphoid differentiation (ustekinumab) and leukocyte trafficking (VDZ, natalizumab). The process of lymphocyte trafficking involves lymphocyte capture, rolling and activation, arrest, adhesion, intravascular crawling and trans migration. Each of these steps is highly regulated with specific adhesion molecules. α4β7-integrin is expressed on lymphocytes that are specific for the gastro intestinal tract. The interaction of α4β7-integrin and MAdCAM-1 on endothelial cells are responsible for the arrest-phase of leukocyte trafficking [12] . In vitro assays of human peripheral blood lymphocytes found that VDZ induces internalization of α4β7-integrin and is rapidly re-expressed and functional after VDZ withdrawal. These assays also demonstrated that there were no adverse effects of VDZ including cytotoxicity, lymphocyte activation and function of memory or regulatory T cells [13] . Natalizumab is a monoclonal antibody against α4, thereby neutralizing both α4β7- and α4β1-integrins. Because of its non-selective nature, natalizumab affects lymphocyte migration to both the gut and the brain. Natalizumab has shown to be effective in treatment of relapsing-remitting multiple sclerosis (MS), likely via inhibition of lymphocyte migration to the brain [14,15] . As well, natalizumab has been shown to be beneficial in the induction and maintenance of CD [16] . However, natalizumab is associated with progressive multifocal leukoencephalopathy (PML) in both MS and CD patients, presumably due to inhibition of leukocyte trafficking to CNS, thereby reducing CNS immune surveillance [17–19] . PML is a rare demyelinating disease of the CNS caused by reactivation of polyomavirus JC (JC virus). It is a disabling disease with high mortality. There have been 398 cases of reported PML
964
Immunotherapy (2014) 6(9)
in all patients treated with natalizumab world wide as of August 2013 [20,21] . VDZ is a humanized G1 monoclonal antibody against the α4β7-integrin heterodimer. Due to the selective antagonism of the α4β7-integrin hetero dimer, VDZ is not expected to have the same risk of PML compared with natalizumab. Design GEMINI 1 inclusion criteria included adult patients with active UC, defined by Mayo Clinical score [22] ≥6 and sigmoidoscopy subscore of ≥2, and ≥15cm of disease from anal verge. GEMINI 2 inclusion criteria selects for adult patients with active CD, defined by CD for at least 3 months with Crohn’s disease activity index (CDAI) [23] of 220–450, and either CRP > 2.87 mg/l, colonoscopic findings ≥3 large ulcers or ≥10 aphthous ulcers or fecal calprotectin >250 μg/g with evidence of ulcers on imaging. GEMINI 1 and 2 limited enrollment with prior TNF-α antagonist failure to 50%. Both trials excluded patients previously exposed to natalizumab, VDZ, efalizumab and rituximab. Patients on concomitant prednisone (or equivalent dose of less than or equal to 30 mg daily), stable immunosuppressants and mesalamine were included in both studies. Glucocorticoids were tapered in patients who had response at week 6 according to a prespecified regimen. Immunosuppressants were maintained at stable dose except for the US sites, where these agents were discontinued after VDZ induction period. Both studies had two cohorts, cohort 1 was randomized for induction trial, while cohort 2 received open-labeled induction and was randomized for maintenance trial. Cohort 1 was randomized 3 to 2 into VDZ 300 mg or placebo respectively at week 0 and week 2, and cohort 2 received open-labeled VDZ 300 mg at week 0 and week 2. Response to therapy was assessed at week 6. Responders from the treatment arm in both cohorts were randomized to VDZ 300 mg every 8 weeks, VDZ 300 mg every 4 weeks or placebo. Nonresponders from the treatment arm received VDZ every 4 weeks. Placebo arm from the induction trial received placebo during the maintenance trial. GEMINI 1 enrolled 374 patients into cohort 1 and 521 patients into cohort 2 from 211 centers in 34 countries. The primary end point in the induction trial was clinical response at week 6, defined by reduction in Mayo Clinical score of at least 3 points and decrease of at least 30% from the baseline score, with decrease of at least 1 point from the rectal bleeding subscale or absolute rectal bleeding score of 0 or 1. The secondary end points in the induction trial were clinical remission at week 6 (defined by Mayo Clinical score of 2 or lower and no subscore higher than 1) and mucosal
future science group
Vedolizumab for ulcerative colitis & Crohn’s disease: results & implications of GEMINI studies
healing (defined by an endoscopic subscore of 0 or 1). The primary end point in the maintenance trial was clinical remission at week 52. The secondary end point in the maintenance trial was durable clinical response, durable clinical remission, mucosal healing and glucocorticoid-free remission at week 52 in patients receiving glucocorticoid at baseline. Durable response or remission was defined as response or remission at both weeks 6 and 52. GEMINI 2 enrolled 368 patients into cohort 1 and 747 patients into cohort 2 from 285 centers in 39 countries. The two co-primary end points in the induction trial were clinical remission (defined a CDAI score of less than or equal to 150) and CDAI-100 response at week 6 (defined as a reduction of CDAI score by at least 100 points). The secondary end point in the induction trial was change in CRP from baseline. The primary end point in the maintenance trial was clinical remission at week 52. The secondary end points in the maintenance trial were CDAI-100 response, glucocorticoid-free remission and durable clinical remission at week 52. Durable remission was defined as clinical remission in at least 80% of study visits including the final visit. Results Patients enrolled in the GEMINI trials and randomized were similar in their baseline characteristics. In GEMINI 1, the average Mayo Clinic score in placebo group was 8.6 ± 1.7 with average duration of disease at 7.1 ± 7.2 years. The average Mayo Clinic score in the combined treatment cohorts was 8.6 ± 1.8 with average duration of disease at 6.8 ± 6.2 years. 33.6% in the placebo group and 37.7% in the combined treatment cohorts had pancolitis. 38.9% were on concomitant glucocorticoids, 12.1% on immunosuppressive agents, and 17.4% were on glucocorticoids and immuno suppressive agents in the placebo group. Approximately 36.7% were on concomitant glucocorticoids, 18.9% on immunosuppressive agents and 16.5% were on glucocorticoids and immunosuppressive agents in the combined treatment cohorts. A total of 49.0 and 48.0% had received prior TNF-α antagonist in the placebo group and combined cohorts, respectively, and of those, 46.0 and 48.4% were primary nonresponders, respectively. In GEMINI 2, the average CDAI score was 325 ± 78 in the placebo group with average duration of disease at 8.2 ± 7.8 years. The average CDAI score was 323 ± 68 in the combined treatment cohorts with average duration of disease at 9.2 ± 7.8 years. Approximately 14.2% had ileal disease only and 56.8% had ileum and colonic disease in the placebo group. Approximately 16.5% had ileal disease only and 55.2% had ileum and colonic disease in the combined treatment cohorts.
future science group
Clinical Trial Report
Approximately 23.0% were current smoker in the placebo group and 27.3% in the combined treatment cohorts. Approximately 30.4% were on concomitant glucocorticoids, 16.9% on immunosuppressive agents and 17.6% were on glucocorticoids and immuno suppressive agents in the placebo group. Approximately 34.7% were on concomitant glucocorticoids, 16.1% on immunosuppressive agents and 16.9% on glucocorticoids and immunosuppressive agents in the combined treatment cohorts. Approximately 48.6 and 63.8% had received prior TNF-α antagonist in the placebo group and combined cohorts, respectively, and of those, 58.6 and 48.5% were primary nonresponders, respectively. GEMINI 1 achieved statistically significant primary and secondary end points in the induction trial by week 6 (Figure 1) . There was clinical response for 25.5% of placebo group and 47.1% of VDZ treatment group (p
![[Current position on Vedolizumab for ulcerative colitis and Crohn's disease].](/assets/img/hold.png)
