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"Patients with moderate-to-severe ulcerative colitis treated with the monoclonal antibody etrolizumab more often achieved clinical remission than those given placebo, a phase II trial found.
Among patients randomized to 100 mg of etrolizumab, 21% (95% CI 7-36) were in remission at week 10, as were 10% (95% CI 0.2-24) of those given 300 mg plus a loading dose of the monoclonal antibody, according to Severine Vermeire, MD, PhD, of the University of Leuven in Belgium, and colleagues.
In contrast, none of the patients randomized to placebo were in clinical remission at that time point (P=0.0040 versus 100 mg and P=0.048 versus 300 mg), the researchers reported online in the Lancet.
In an accompanying comment, Alessandro Armuzzi, MD, and Carla Felice, MD, of Catholic University in Rome, noted that the benefits seen in this refractory group of patients, many of whom had not responded to immunosuppressants and tumor necrosis factor (TNF) inhibitors, suggests that "etrolizumab has great potential to become a new therapeutic option for patients with ulcerative colitis."
"Inhibition of the interaction of the alpha-4-beta-7 integrin with its ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), interferes with immune-cell trafficking into the intestine and is an effective therapy for both ulcerative colitis and Crohn's disease," the investigators explained.
Etrolizumab binds the beta-7 subunit of the integrins alpha-4-beta-7 and alpha-E-beta-7, preventing the migration of lymphocytes from blood vessels in the mucosa to the gut.
Because a previous phase 1 study found that etrolizumab did inhibit this lymphocyte migration and blocked the interaction between alpha-E-beta-7 and E-cadherin, Vermeire and colleagues enrolled 124 patients with moderate-to-severe active ulcerative colitis who had not responded to standard treatments.
Mean age was about 40 and disease duration was 9 years. Mean Mayo Clinic score at baseline was 9.2.
Clinical remission was defined as a Mayo Clinic score of 2 or less and no subscores greater than 1. Clinical response was defined as a 3-point decrease and 30% improvement on the Mayo Clinic score, plus a 1-point decline in rectal bleeding score.
The 100 mg dose was given at baseline and weeks four and eight, while the 300 mg dose was given at weeks two, four, and eight following a loading dose of 420 mg at baseline.
For clinical remission at week six, no difference was seen between the groups, with 10% of the 100 mg group, 8% of the 300 mg group, and 5% of the placebo group achieving that endpoint.
Clinical responses at week six were seen in 49% and 38% of the 100 mg and 300 mg etrolizumab groups and in 34% of the placebo group, while clinical responses at week 10 in the three groups were 33%, 31%, and 29%, respectively.
Among patients who were taking concomitant steroids, 33% of the 100 mg group were in clinical remission at week 10 compared with none of the placebo patients (P<0.01). For those not receiving immunomodulators, 23% of the 10 mg group had achieved clinical remission at week 10 compared with none of the placebo group (P<0.05).
And among those who had never received TNF blockers, 44% were in remission at week 10 compared with none of the placebo group (P<0.01).
In an exploratory analysis, 26% of patients in the 100 mg group had healing of the intestinal mucosa at week 10, as did 21% of the 300 mg group and 15% of the placebo group.
In an additional post-hoc analysis, more patients with high gene expression of alpha-E-beta-7 on a baseline biopsy of colonic tissue reached remission. This finding will be further examined in additional trials as a potential biomarker for response.
Serious adverse events occurred in 12% of the 100 mg and placebo groups and in 5% of the 300 mg group. Patients in the 100 mg group more often had influenza-like illnesses, arthralgias, and rash than the other two groups.
There were no cases of progressive multifocal leukoencephalopathy.
Complete occupancy of beta-7 receptors was seen both in colonic tissue and peripheral blood.
However, "a clinical benefit was not found in all patients, suggesting that the inflammatory process continues in some patients despite blockade of the beta-7 receptor. This finding could be explained by the proinflammatory activity of immune cells already present in the gut before treatment with etrolizumab, or a potential beta-7 independent mechanism of leukocyte trafficking to the intestinal mucosa," the researchers wrote.
As to why the higher dose of the monoclonal antibody appeared to be less effective than the lower dose, the investigators suggested that this may be related to alterations in the migration of other types of cells such as regulatory T cells.
"Further prospective studies will be important to better elucidate the effect of etrolizumab on the trafficking and function of various alpha-4-beta-7 expressing and alpha-E-beta-7 expressing immune cells," they concluded.
Phase III trials will begin soon, co-author William J. Sandborn, MD, told MedPage Today.
"We have not had a biologic with a new mechanism of action since 1998, when the first anti-TNF antibody, infliximab [Remicade] was approved for Crohn's disease," explained Sandborn, who is director of the inflammatory bowel disease center, University of California San Diego.
"We anticipate FDA approval of the first selective anti-integrin antibody, vedolizumab (anti-alpha-4-beta-7) for both Crohn's disease and ulcerative colitis in late May. With the anti-TNF drugs, having multiple medications available in the class has been of great value for physicians and patients. We expect that the same will be true for the selective anti-integrin class, which includes etrolizumab, AMG181 (another anti-beta-7 antibody), and anti-MAdCAM-1 antibody," Sandborn said."
http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/45745
Among patients randomized to 100 mg of etrolizumab, 21% (95% CI 7-36) were in remission at week 10, as were 10% (95% CI 0.2-24) of those given 300 mg plus a loading dose of the monoclonal antibody, according to Severine Vermeire, MD, PhD, of the University of Leuven in Belgium, and colleagues.
In contrast, none of the patients randomized to placebo were in clinical remission at that time point (P=0.0040 versus 100 mg and P=0.048 versus 300 mg), the researchers reported online in the Lancet.
In an accompanying comment, Alessandro Armuzzi, MD, and Carla Felice, MD, of Catholic University in Rome, noted that the benefits seen in this refractory group of patients, many of whom had not responded to immunosuppressants and tumor necrosis factor (TNF) inhibitors, suggests that "etrolizumab has great potential to become a new therapeutic option for patients with ulcerative colitis."
"Inhibition of the interaction of the alpha-4-beta-7 integrin with its ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), interferes with immune-cell trafficking into the intestine and is an effective therapy for both ulcerative colitis and Crohn's disease," the investigators explained.
Etrolizumab binds the beta-7 subunit of the integrins alpha-4-beta-7 and alpha-E-beta-7, preventing the migration of lymphocytes from blood vessels in the mucosa to the gut.
Because a previous phase 1 study found that etrolizumab did inhibit this lymphocyte migration and blocked the interaction between alpha-E-beta-7 and E-cadherin, Vermeire and colleagues enrolled 124 patients with moderate-to-severe active ulcerative colitis who had not responded to standard treatments.
Mean age was about 40 and disease duration was 9 years. Mean Mayo Clinic score at baseline was 9.2.
Clinical remission was defined as a Mayo Clinic score of 2 or less and no subscores greater than 1. Clinical response was defined as a 3-point decrease and 30% improvement on the Mayo Clinic score, plus a 1-point decline in rectal bleeding score.
The 100 mg dose was given at baseline and weeks four and eight, while the 300 mg dose was given at weeks two, four, and eight following a loading dose of 420 mg at baseline.
For clinical remission at week six, no difference was seen between the groups, with 10% of the 100 mg group, 8% of the 300 mg group, and 5% of the placebo group achieving that endpoint.
Clinical responses at week six were seen in 49% and 38% of the 100 mg and 300 mg etrolizumab groups and in 34% of the placebo group, while clinical responses at week 10 in the three groups were 33%, 31%, and 29%, respectively.
Among patients who were taking concomitant steroids, 33% of the 100 mg group were in clinical remission at week 10 compared with none of the placebo patients (P<0.01). For those not receiving immunomodulators, 23% of the 10 mg group had achieved clinical remission at week 10 compared with none of the placebo group (P<0.05).
And among those who had never received TNF blockers, 44% were in remission at week 10 compared with none of the placebo group (P<0.01).
In an exploratory analysis, 26% of patients in the 100 mg group had healing of the intestinal mucosa at week 10, as did 21% of the 300 mg group and 15% of the placebo group.
In an additional post-hoc analysis, more patients with high gene expression of alpha-E-beta-7 on a baseline biopsy of colonic tissue reached remission. This finding will be further examined in additional trials as a potential biomarker for response.
Serious adverse events occurred in 12% of the 100 mg and placebo groups and in 5% of the 300 mg group. Patients in the 100 mg group more often had influenza-like illnesses, arthralgias, and rash than the other two groups.
There were no cases of progressive multifocal leukoencephalopathy.
Complete occupancy of beta-7 receptors was seen both in colonic tissue and peripheral blood.
However, "a clinical benefit was not found in all patients, suggesting that the inflammatory process continues in some patients despite blockade of the beta-7 receptor. This finding could be explained by the proinflammatory activity of immune cells already present in the gut before treatment with etrolizumab, or a potential beta-7 independent mechanism of leukocyte trafficking to the intestinal mucosa," the researchers wrote.
As to why the higher dose of the monoclonal antibody appeared to be less effective than the lower dose, the investigators suggested that this may be related to alterations in the migration of other types of cells such as regulatory T cells.
"Further prospective studies will be important to better elucidate the effect of etrolizumab on the trafficking and function of various alpha-4-beta-7 expressing and alpha-E-beta-7 expressing immune cells," they concluded.
Phase III trials will begin soon, co-author William J. Sandborn, MD, told MedPage Today.
"We have not had a biologic with a new mechanism of action since 1998, when the first anti-TNF antibody, infliximab [Remicade] was approved for Crohn's disease," explained Sandborn, who is director of the inflammatory bowel disease center, University of California San Diego.
"We anticipate FDA approval of the first selective anti-integrin antibody, vedolizumab (anti-alpha-4-beta-7) for both Crohn's disease and ulcerative colitis in late May. With the anti-TNF drugs, having multiple medications available in the class has been of great value for physicians and patients. We expect that the same will be true for the selective anti-integrin class, which includes etrolizumab, AMG181 (another anti-beta-7 antibody), and anti-MAdCAM-1 antibody," Sandborn said."
http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/45745
