ICYMI Multiple Sclerosis

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants "was too small to demonstrate efficacy at the 50% level," said Samia J. Khoury, MD, senior neurologist at Brigham and Women's Hospital in Boston, and her colleagues. "Low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept." A prior phase II trial of abatacept that was stopped early as a result of safety events yielded inconclusive results because of an imbalance in the participants' baseline disease activity.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants "was too small to demonstrate efficacy at the 50% level," said Samia J. Khoury, MD, senior neurologist at Brigham and Women's Hospital in Boston, and her colleagues. "Low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept." A prior phase II trial of abatacept that was stopped early as a result of safety events yielded inconclusive results because of an imbalance in the participants' baseline disease activity.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants "was too small to demonstrate efficacy at the 50% level," said Samia J. Khoury, MD, senior neurologist at Brigham and Women's Hospital in Boston, and her colleagues. "Low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept." A prior phase II trial of abatacept that was stopped early as a result of safety events yielded inconclusive results because of an imbalance in the participants' baseline disease activity.

—Jeff Evans

Results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study indicate that abatacept has no effect on reducing the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis, according to Samia J. Khoury, MD, of Brigham and Women’s Hospital, Boston, and her colleagues from the Immune Tolerance Network.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 for 20 placebo-treated patients (P = .87). None of the secondary MRI endpoints (lesion volume change and percent brain volume change) and clinical endpoints (changes in Multiple Sclerosis Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

 

©solitude72/iStockphoto

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs. 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by targeting the adaptive arm of the immune system by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting multiple sclerosis because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 total patients who enrolled in the trial were about half of the number designated in the trial design (n = 123) in order to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants “was too small to demonstrate efficacy at the 50% level,” the investigators wrote, and “low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept.”

A prior phase II trial of abatacept that was stopped early due to safety events yielded inconclusive results because of an imbalance in the baseline disease activity of participants.

Read the full report online in Multiple Sclerosis Journal (Mult Scler J. 2016 Aug 1. doi: 10.1177/1352458516662727).

jevans@frontlinemedcom.com

Results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study indicate that abatacept has no effect on reducing the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis, according to Samia J. Khoury, MD, of Brigham and Women’s Hospital, Boston, and her colleagues from the Immune Tolerance Network.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 for 20 placebo-treated patients (P = .87). None of the secondary MRI endpoints (lesion volume change and percent brain volume change) and clinical endpoints (changes in Multiple Sclerosis Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

 

©solitude72/iStockphoto

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs. 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by targeting the adaptive arm of the immune system by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting multiple sclerosis because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 total patients who enrolled in the trial were about half of the number designated in the trial design (n = 123) in order to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants “was too small to demonstrate efficacy at the 50% level,” the investigators wrote, and “low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept.”

A prior phase II trial of abatacept that was stopped early due to safety events yielded inconclusive results because of an imbalance in the baseline disease activity of participants.

Read the full report online in Multiple Sclerosis Journal (Mult Scler J. 2016 Aug 1. doi: 10.1177/1352458516662727).

jevans@frontlinemedcom.com

Results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study indicate that abatacept has no effect on reducing the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis, according to Samia J. Khoury, MD, of Brigham and Women’s Hospital, Boston, and her colleagues from the Immune Tolerance Network.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 for 20 placebo-treated patients (P = .87). None of the secondary MRI endpoints (lesion volume change and percent brain volume change) and clinical endpoints (changes in Multiple Sclerosis Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

 

©solitude72/iStockphoto

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs. 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by targeting the adaptive arm of the immune system by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting multiple sclerosis because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 total patients who enrolled in the trial were about half of the number designated in the trial design (n = 123) in order to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

The number of participants “was too small to demonstrate efficacy at the 50% level,” the investigators wrote, and “low numbers of new gadolinium-enhancing MRI lesions in the study population reduced the chances of demonstrating a treatment effect for abatacept.”

A prior phase II trial of abatacept that was stopped early due to safety events yielded inconclusive results because of an imbalance in the baseline disease activity of participants.

Read the full report online in Multiple Sclerosis Journal (Mult Scler J. 2016 Aug 1. doi: 10.1177/1352458516662727).

jevans@frontlinemedcom.com

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

 

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

 

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

VANCOUVER—MD1003, a pharmaceutical-grade formulation of biotin, reverses disease progression in a significant proportion of patients with progressive multiple sclerosis (MS), according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug is safe and remains effective throughout two years of treatment. Delayed treatment with MD1003 is beneficial, but the delay results in higher levels of disability, compared with immediate treatment.

The drug, however, does not significantly improve visual acuity, compared with placebo, in patients with relapsing-remitting or progressive MS and chronic optic neuropathy, said Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France.

MD1003 and Disease Progression

To investigate MD1003’s effect on disease progression in patients with progressive MS, Dr. Tourbah and colleagues conducted a placebo-controlled, double-blind study. Eligible patients had primary or secondary progressive MS and an Expanded Disability Status Scale (EDSS) score between 4.5 and 7. In addition, participants had to have had disease progression in the previous two years without evidence of clinical or MRI inflammatory activity within the previous year.

In the first phase of the trial, which lasted for 12 months, patients were randomized 2:1 to MD1003 or placebo. A 12-month extension phase followed, in which all patients received MD1003. Patients and clinicians remained blinded to the treatment assignments of the double-blind phase. The trial’s primary end point was the proportion of patients that improved at month nine and had confirmed improvement at month 12 on EDSS or the Timed 25-Foot Walk, compared with the best baseline measures.

In all, 103 patients were randomized to MD1003, and 51 patients were randomized to placebo. Ninety-one patients from the MD1003 group entered the extension phase, along with 42 patients from the placebo group. In the extension phase, 17 patients originally assigned to MD1003 and four patients originally assigned to placebo discontinued treatment. The main reason for discontinuation in both arms was consent withdrawal.

At baseline, the researchers observed no major differences between treatment arms with regard to sex ratio, mean age, mean disease duration, and mean EDSS score. Slightly more patients in the MD1003 arm had primary progressive MS than in the placebo arm. Approximately 40% of patients were taking concomitant disease-modifying therapies.

In the double-blind phase, 12.6% of patients receiving MD1003 had improvement at month nine and confirmed improvement at month 12. No patient receiving placebo had these outcomes, and the difference between groups was statistically significant. In the extension phase, treatment efficacy was maintained among patients randomized to MD1003 and became apparent in patients who were switched from placebo to MD1003. The level of disability remained higher in the latter group, however.

The rate of adverse events was consistent from the trial’s double-blind phase through its extension phase. The most frequent side effects were infections and infestations and disorders involving the nervous, gastrointestinal, musculoskeletal, and connective tissue systems. Patients originally randomized to placebo did not have more adverse events after switching to MD1003. A few cases of apparent hyperthyroidism were encountered. These are known to be related to interferences between high doses of biotin and biotin-based laboratory tests. Two cases of neoplasm were reported in the extension phase and were not reported as related to the treatment.

“This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients,” said Dr. Tourbah. “Almost no progression was observed in patients treated with MD1003 for 24 months, and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed.”

MD1003 and Visual Acuity

In a separate study, Dr. Tourbah and colleagues analyzed the efficacy of MD1003, compared with placebo, in patients with relapsing-remitting or progressive MS and visual loss related to chronic optic neuropathy. Eligible participants had at least one eye with confirmed visual acuity of 20/40 or less on a standard chart, and worsening of visual acuity within the previous three years. The investigators categorized patients as having progressive optic neuropathy (ie, progressive visual loss observed at two separate ophthalmologic examinations within the three years preceding inclusion) or nonprogressive optic neuropathy (ie, a fixed visual loss for six months or more following an episode of acute optic neuritis).

Patients were randomized 2:1 to MD1003 or placebo for six months. In a subsequent six-month extension phase, patients on placebo were switched to MD1003. Patients and clinicians remained blinded to the treatments that had been given in the double-blind phase. The primary end point was the mean change in visual acuity between month zero and month six in the eye with worse visual acuity at baseline and visual worsening within the previous three years. Dr. Tourbah and colleagues used the Early Treatment Diabetic Retinopathy Study chart at 100% to evaluate visual acuity.

 

In all, 65 patients were randomized to MD1003, and 28 patients to placebo. One patient did not enter the extension phase of the trial. Demographic characteristics were similar in the two treatment arms, but the majority of patients had nonprogressive chronic optic neuropathy, especially in the placebo arm. Slightly more patients randomized to MD1003 were taking disease-modifying therapies, compared with the placebo arm.

At six months, visual acuity improved in all patients. Improvement was more pronounced in patients receiving MD1003, but the difference between groups was not statistically significant. When the investigators examined only patients with nonprogressive chronic optic neuropathy, they found no difference between treatment groups at six months. When they examined participants with progressive chronic optic neuropathy, however, patients randomized to MD1003 had improved visual acuity at six months, while patients randomized to placebo had worsened visual acuity.

In the extension phase, patients who had improved on placebo continued to improve after switching to MD1003, and patients who had improved on MD1003 continued to improve. The researchers saw no differences in visual acuity between groups at 12 months. Among participants with nonprogressive chronic optic neuropathy, visual acuity improved in both treatment arms, and the researchers saw little difference between them at 12 months. Among patients with progressive chronic optic neuropathy, disease progression stopped in participants who switched from placebo to MD1003.

These results suggest that the treatment has no indication in patients with relapsing-remitting MS and show a trend toward efficacy in patients with progressive chronic optic neuropathy, which is consistent with the results of the MS-SPI study.

In addition, Dr. Tourbah and colleagues observed no major differences between treatment arms regarding the most frequent adverse events (ie, infections and infestations, nervous system disorders, and intestinal disorders). They noted, however, that more patients receiving MD1003 had relapses, compared with patients receiving placebo. “Whether MD1003 may trigger exacerbations in patients with relapsing-remitting MS deserves further investigation,” Dr. Tourbah concluded.

—Erik Greb

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

Once-daily oral siponimod was associated with sustained effects on MRI outcomes at 24 months in patients with relapsing-remitting multiple sclerosis in a dose-blinded extension of the phase II study.

Disease activity was low, “with some evidence of greater benefit associated with siponimod at 10-mg, 2-mg, and 1.25-mg doses than with siponimod at 0.25-mg and 0.5-mg doses. No new safety signals emerged, and dose titration at treatment initiation mitigated cardiac effects,” Ludwig Kappos, MD, of University Hospital Basel (Switzerland), and his associates wrote in JAMA Neurology. “With similar efficacy but lower rates of lymphopenia relative to the 10-mg dose, siponimod 2 mg, has been chosen for further development,” they wrote.

Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor (S1P_1,5) modulator that was evaluated for up to 6 months at five doses in the phase II BOLD (BAF312 on MRI Lesion Given Once Daily) study. Patients with relapsing-remitting MS who received 10 mg siponimod had up to 80% reductions in MRI combined unique active lesions (CUALs, or gadolinium-enhancing T1 lesions and/or new and newly enlarging T2 lesions, without double counting), compared with the placebo group. The 2-mg and 0.5-mg dose cohorts had reductions of 72% and 50%, respectively. The current study was a 24-month, dose-blinded extension phase that included 185 participants (73% of 252 eligible patients), of whom 33 patients received 10 mg siponimod, 29 received 2 mg, 43 received 1.25 mg, 29 received 0.5 mg, and 50 received 0.25 mg (JAMA Neurol. 2016 July 5. doi: 10.1001/jamaneurol.2016.1451).

Average reductions in gadolinium-enhancing T1 lesion counts were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups at month 24, the researchers reported. The 1.25-mg and 2-mg doses yielded the highest proportions of patients free from new MRI activity (58% for both dose groups) and free from new or newly enlarging T2 lesions (61% and 58%, respectively). New or newly enlarging T2 lesions were numerically lower at doses exceeding 0.25 mg. “There were no clear changes in normalized brain volume within or between any of the treatment groups,” the investigators added.

Dose titration during the first 10 days of treatment mitigated bradycardia and atrioventricular conduction effects. Rates of adverse events within dose groups ranged from 84% to 97% and did not show a trend with dose size. Serious adverse events affected nine patients (5%) and included one case each of otosclerosis, gastritis, anaphylaxis, acute pyelonephritis, femoral and ankle fractures, basal cell carcinoma, cervical neoplasm, and abortion. Thirteen patients (7%) required treatment interruptions because of adverse events, of which seven consisted of lymphopenia or decreased lymphocyte count at the 10-mg dose. Other adverse events leading to dose interruptions or adjustments included neutropenia, upper respiratory tract infection, elevated hepatic transaminases, and hypertension.

Novartis is developing siponimod and funded the study. Coinvestigators employed by Novartis participated in all aspects of the study, including interpretation of the data and manuscript submission. Dr. Kappos disclosed financial ties to Novartis and numerous other pharmaceutical companies, foundations, and societies.

NATIONAL HARBOR, MD—High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation induces a high rate of remission among patients with highly active relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting. Furthermore, that remission is sustained for five years without maintenance therapy. "We saw about 70% long-term, disease-free survival at five years," said Richard A. Nash, MD, a physician at Colorado Blood Cancer Institute in Denver and a HALT-MS investigator.

Richard A. Nash, MD

“What we studied was high-dose therapy, followed by transplant, for treatment of patients with poor-prognosis MS,” said Dr. Nash on behalf of his study collaborators. Their hypothesis was that intensive immunosuppressive therapy followed by transplant would arrest MS disease activity. Their phase II multicenter study had a prospective, open-label, single-arm design. There were three centers involved—Baylor College of Medicine in Houston, the Fred Hutchinson Cancer Research Center in Seattle, and the Ohio State University MS Center in Columbus.

The aim of the study was to determine the five-year durability of disease stabilization in patients with MS after high-dose therapy and autologous transplantation. An interim analysis at three years was published in JAMA Neurology.

The primary end point was event-free survival after transplant in the five-year period of follow-up. The end point included relapse, defined as neurologic signs or symptoms lasting more than 48 hours; MRI abnormalities at more than 12 months after transplant; progression in disability after six months post-transplant (as measured by Expanded Disability Status Scale or EDSS); and mortality. The end point was similar to no evidence of disease activity (NEDA), said Dr. Nash.

Patients who were eligible for the study were age 18 to 60, met McDonald criteria, and had had MS for less than 15 years. Patients had relapsing-remitting MS with cumulative disability or progressive-relapsing MS. EDSS score had to be between 3.0 and 5.5. Patients had to have T2 abnormalities consistent with MS and two or more relapses within 18 months on therapy, with an EDSS increase of more than 0.5. “I don’t think we had anyone in the study that met the second criterion, which was relapse on therapy with an EDSS increase of more than 1.0 and one separate event with gadolinium-enhancing lesions on MRI,” Dr. Nash said. A panel of two neurologists and one transplant physician reviewed the patients.

There were 25 patients in the HALT-MS trial. Median age at mobilization was 37 (range, 26 to 52). The study cohort was mostly female (17 female, 8 male). Baseline EDSS score was 4.5 (range, 3.0 to 5.5). Median disease duration was 4.9 years (range, seven months to 12 years). Therapies that patients had failed prior to study entry included interferon beta-1a (22 patients), interferon beta-1b (one patient), glatiramer acetate (18 patients), mitoxantrone (eight patients), natalizumab (six patients), and other therapies (11 patients).

James D. Bowen, MD, of the Swedish Neuroscience Institute in Seattle and a HALT-MS investigator, described the study intervention. “The protocol starts with mobilization of stem cells. Patients receive prednisone during this time so that the CSF is not vulnerable to MS attack. They then undergo leukapheresis to collect stem cells, which are further concentrated with a CD34 selection procedure that allows us to purify them.” Most patients with cancer require four or five pheresis sessions, Dr. Bowen noted, but patients with MS generally have healthy bone marrow, so most of the participants in HALT-MS only required two sessions. A few required three pheresis sessions.

“For our transplant protocol, we used BEAM plus ATG, which is a five-drug cocktail—BCNU, etoposide, Ara C, melphalan, and rabbit antithymocyte globulin,” said Dr. Bowen. “Immediately following that, transplant of the stem cells was done. After that, they got granulocyte-colony stimulating factor (G-CSF) to rev up the bone marrow, and we cover that with prednisone at days seven to 21 to avoid MS attacks precipitated by graft syndrome.”

Twenty-four patients went on to transplant. One of the patients had a pulmonary embolus and was not deemed a good candidate for transplantation. The rate of event-free survival, the primary end point, was 69.2%. Seven patients met the primary end point: two by progression of their disease, three by relapse of their disease, and two patients met end points much later in the follow-up, by changes in their MRI at 3.5 to 4.0 years.

The rate of five-year relapse-free survival was 86.9%. Two patients had changes on MRI. The two patients met primary end points and had their disease activity about 3.5 years after transplant. “There was an early event as well, at one year, but the patient who had MRI changes at one year had already met a primary end point by relapsing at about six months,” Dr. Nash said. The rate of disease progression-free survival was 91%.

 

Regarding change from baseline in T1 and T2 lesion volume, “we had very low incidence, except for two patients who at about 3.5 to 4.0 years after transplant became positive,” Dr. Nash reported. No other patients had development of significant lesions. The T2 lesion volume actually decreased over time and remained decreased through the five years of follow-up. Starting at about three years after transplantation, the researchers noted stability of brain volume.

The researchers recorded three deaths that were considered to be unrelated to the transplant. Two deaths were thought to be possibly related to progression of MS, and one death was in a patient who had evidence of asthma prior to transplant. “That patient was seen by pulmonary medicine, and it was thought that the patient was reasonable to go on to transplant, but the patient had persistent problems after transplant and died at about four years after the transplant,” Dr. Nash said.

The transplant itself appeared to be well tolerated. “There were few serious complications other than what we might expect from a transplant,” Dr. Nash said. It was highly effective for inducing sustained remission for highly active patients with relapsing-remitting MS through five years, and these patients have not received any maintenance therapy since the transplant. MRI lesion volume was reduced, and the brain volume stabilized at years three through five.

The HALT-MS study was sponsored by the National Institute of Allergy & Infectious Diseases (NIAID) and run by the Immune Tolerance Network.

—Glenn S. Williams

NATIONAL HARBOR, MD—High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation induces a high rate of remission among patients with highly active relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting. Furthermore, that remission is sustained for five years without maintenance therapy. "We saw about 70% long-term, disease-free survival at five years," said Richard A. Nash, MD, a physician at Colorado Blood Cancer Institute in Denver and a HALT-MS investigator.

Richard A. Nash, MD

“What we studied was high-dose therapy, followed by transplant, for treatment of patients with poor-prognosis MS,” said Dr. Nash on behalf of his study collaborators. Their hypothesis was that intensive immunosuppressive therapy followed by transplant would arrest MS disease activity. Their phase II multicenter study had a prospective, open-label, single-arm design. There were three centers involved—Baylor College of Medicine in Houston, the Fred Hutchinson Cancer Research Center in Seattle, and the Ohio State University MS Center in Columbus.

The aim of the study was to determine the five-year durability of disease stabilization in patients with MS after high-dose therapy and autologous transplantation. An interim analysis at three years was published in JAMA Neurology.

The primary end point was event-free survival after transplant in the five-year period of follow-up. The end point included relapse, defined as neurologic signs or symptoms lasting more than 48 hours; MRI abnormalities at more than 12 months after transplant; progression in disability after six months post-transplant (as measured by Expanded Disability Status Scale or EDSS); and mortality. The end point was similar to no evidence of disease activity (NEDA), said Dr. Nash.

Patients who were eligible for the study were age 18 to 60, met McDonald criteria, and had had MS for less than 15 years. Patients had relapsing-remitting MS with cumulative disability or progressive-relapsing MS. EDSS score had to be between 3.0 and 5.5. Patients had to have T2 abnormalities consistent with MS and two or more relapses within 18 months on therapy, with an EDSS increase of more than 0.5. “I don’t think we had anyone in the study that met the second criterion, which was relapse on therapy with an EDSS increase of more than 1.0 and one separate event with gadolinium-enhancing lesions on MRI,” Dr. Nash said. A panel of two neurologists and one transplant physician reviewed the patients.

There were 25 patients in the HALT-MS trial. Median age at mobilization was 37 (range, 26 to 52). The study cohort was mostly female (17 female, 8 male). Baseline EDSS score was 4.5 (range, 3.0 to 5.5). Median disease duration was 4.9 years (range, seven months to 12 years). Therapies that patients had failed prior to study entry included interferon beta-1a (22 patients), interferon beta-1b (one patient), glatiramer acetate (18 patients), mitoxantrone (eight patients), natalizumab (six patients), and other therapies (11 patients).

James D. Bowen, MD, of the Swedish Neuroscience Institute in Seattle and a HALT-MS investigator, described the study intervention. “The protocol starts with mobilization of stem cells. Patients receive prednisone during this time so that the CSF is not vulnerable to MS attack. They then undergo leukapheresis to collect stem cells, which are further concentrated with a CD34 selection procedure that allows us to purify them.” Most patients with cancer require four or five pheresis sessions, Dr. Bowen noted, but patients with MS generally have healthy bone marrow, so most of the participants in HALT-MS only required two sessions. A few required three pheresis sessions.

“For our transplant protocol, we used BEAM plus ATG, which is a five-drug cocktail—BCNU, etoposide, Ara C, melphalan, and rabbit antithymocyte globulin,” said Dr. Bowen. “Immediately following that, transplant of the stem cells was done. After that, they got granulocyte-colony stimulating factor (G-CSF) to rev up the bone marrow, and we cover that with prednisone at days seven to 21 to avoid MS attacks precipitated by graft syndrome.”

Twenty-four patients went on to transplant. One of the patients had a pulmonary embolus and was not deemed a good candidate for transplantation. The rate of event-free survival, the primary end point, was 69.2%. Seven patients met the primary end point: two by progression of their disease, three by relapse of their disease, and two patients met end points much later in the follow-up, by changes in their MRI at 3.5 to 4.0 years.

The rate of five-year relapse-free survival was 86.9%. Two patients had changes on MRI. The two patients met primary end points and had their disease activity about 3.5 years after transplant. “There was an early event as well, at one year, but the patient who had MRI changes at one year had already met a primary end point by relapsing at about six months,” Dr. Nash said. The rate of disease progression-free survival was 91%.

 

Regarding change from baseline in T1 and T2 lesion volume, “we had very low incidence, except for two patients who at about 3.5 to 4.0 years after transplant became positive,” Dr. Nash reported. No other patients had development of significant lesions. The T2 lesion volume actually decreased over time and remained decreased through the five years of follow-up. Starting at about three years after transplantation, the researchers noted stability of brain volume.

The researchers recorded three deaths that were considered to be unrelated to the transplant. Two deaths were thought to be possibly related to progression of MS, and one death was in a patient who had evidence of asthma prior to transplant. “That patient was seen by pulmonary medicine, and it was thought that the patient was reasonable to go on to transplant, but the patient had persistent problems after transplant and died at about four years after the transplant,” Dr. Nash said.

The transplant itself appeared to be well tolerated. “There were few serious complications other than what we might expect from a transplant,” Dr. Nash said. It was highly effective for inducing sustained remission for highly active patients with relapsing-remitting MS through five years, and these patients have not received any maintenance therapy since the transplant. MRI lesion volume was reduced, and the brain volume stabilized at years three through five.

The HALT-MS study was sponsored by the National Institute of Allergy & Infectious Diseases (NIAID) and run by the Immune Tolerance Network.

—Glenn S. Williams

NATIONAL HARBOR, MD—High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation induces a high rate of remission among patients with highly active relapsing-remitting multiple sclerosis (MS), according to data presented at the 2016 CMSC Annual Meeting. Furthermore, that remission is sustained for five years without maintenance therapy. "We saw about 70% long-term, disease-free survival at five years," said Richard A. Nash, MD, a physician at Colorado Blood Cancer Institute in Denver and a HALT-MS investigator.

Richard A. Nash, MD

“What we studied was high-dose therapy, followed by transplant, for treatment of patients with poor-prognosis MS,” said Dr. Nash on behalf of his study collaborators. Their hypothesis was that intensive immunosuppressive therapy followed by transplant would arrest MS disease activity. Their phase II multicenter study had a prospective, open-label, single-arm design. There were three centers involved—Baylor College of Medicine in Houston, the Fred Hutchinson Cancer Research Center in Seattle, and the Ohio State University MS Center in Columbus.

The aim of the study was to determine the five-year durability of disease stabilization in patients with MS after high-dose therapy and autologous transplantation. An interim analysis at three years was published in JAMA Neurology.

The primary end point was event-free survival after transplant in the five-year period of follow-up. The end point included relapse, defined as neurologic signs or symptoms lasting more than 48 hours; MRI abnormalities at more than 12 months after transplant; progression in disability after six months post-transplant (as measured by Expanded Disability Status Scale or EDSS); and mortality. The end point was similar to no evidence of disease activity (NEDA), said Dr. Nash.

Patients who were eligible for the study were age 18 to 60, met McDonald criteria, and had had MS for less than 15 years. Patients had relapsing-remitting MS with cumulative disability or progressive-relapsing MS. EDSS score had to be between 3.0 and 5.5. Patients had to have T2 abnormalities consistent with MS and two or more relapses within 18 months on therapy, with an EDSS increase of more than 0.5. “I don’t think we had anyone in the study that met the second criterion, which was relapse on therapy with an EDSS increase of more than 1.0 and one separate event with gadolinium-enhancing lesions on MRI,” Dr. Nash said. A panel of two neurologists and one transplant physician reviewed the patients.

There were 25 patients in the HALT-MS trial. Median age at mobilization was 37 (range, 26 to 52). The study cohort was mostly female (17 female, 8 male). Baseline EDSS score was 4.5 (range, 3.0 to 5.5). Median disease duration was 4.9 years (range, seven months to 12 years). Therapies that patients had failed prior to study entry included interferon beta-1a (22 patients), interferon beta-1b (one patient), glatiramer acetate (18 patients), mitoxantrone (eight patients), natalizumab (six patients), and other therapies (11 patients).

James D. Bowen, MD, of the Swedish Neuroscience Institute in Seattle and a HALT-MS investigator, described the study intervention. “The protocol starts with mobilization of stem cells. Patients receive prednisone during this time so that the CSF is not vulnerable to MS attack. They then undergo leukapheresis to collect stem cells, which are further concentrated with a CD34 selection procedure that allows us to purify them.” Most patients with cancer require four or five pheresis sessions, Dr. Bowen noted, but patients with MS generally have healthy bone marrow, so most of the participants in HALT-MS only required two sessions. A few required three pheresis sessions.

“For our transplant protocol, we used BEAM plus ATG, which is a five-drug cocktail—BCNU, etoposide, Ara C, melphalan, and rabbit antithymocyte globulin,” said Dr. Bowen. “Immediately following that, transplant of the stem cells was done. After that, they got granulocyte-colony stimulating factor (G-CSF) to rev up the bone marrow, and we cover that with prednisone at days seven to 21 to avoid MS attacks precipitated by graft syndrome.”

Twenty-four patients went on to transplant. One of the patients had a pulmonary embolus and was not deemed a good candidate for transplantation. The rate of event-free survival, the primary end point, was 69.2%. Seven patients met the primary end point: two by progression of their disease, three by relapse of their disease, and two patients met end points much later in the follow-up, by changes in their MRI at 3.5 to 4.0 years.

The rate of five-year relapse-free survival was 86.9%. Two patients had changes on MRI. The two patients met primary end points and had their disease activity about 3.5 years after transplant. “There was an early event as well, at one year, but the patient who had MRI changes at one year had already met a primary end point by relapsing at about six months,” Dr. Nash said. The rate of disease progression-free survival was 91%.

 

Regarding change from baseline in T1 and T2 lesion volume, “we had very low incidence, except for two patients who at about 3.5 to 4.0 years after transplant became positive,” Dr. Nash reported. No other patients had development of significant lesions. The T2 lesion volume actually decreased over time and remained decreased through the five years of follow-up. Starting at about three years after transplantation, the researchers noted stability of brain volume.

The researchers recorded three deaths that were considered to be unrelated to the transplant. Two deaths were thought to be possibly related to progression of MS, and one death was in a patient who had evidence of asthma prior to transplant. “That patient was seen by pulmonary medicine, and it was thought that the patient was reasonable to go on to transplant, but the patient had persistent problems after transplant and died at about four years after the transplant,” Dr. Nash said.

The transplant itself appeared to be well tolerated. “There were few serious complications other than what we might expect from a transplant,” Dr. Nash said. It was highly effective for inducing sustained remission for highly active patients with relapsing-remitting MS through five years, and these patients have not received any maintenance therapy since the transplant. MRI lesion volume was reduced, and the brain volume stabilized at years three through five.

The HALT-MS study was sponsored by the National Institute of Allergy & Infectious Diseases (NIAID) and run by the Immune Tolerance Network.

—Glenn S. Williams

VANCOUVER—Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently reduces relapses, disability progression, and new or enlarging lesions, compared with interferon beta-1a, in patients with relapsing-remitting multiple sclerosis (MS), according to two phase III trials reported at the 68th Annual Meeting of the American Academy of Neurology.

OPERA I and OPERA II

The identical trials, dubbed OPERA I and OPERA II, each included about 800 patients. Subjects were randomized one-to-one to 600 mg of IV ocrelizumab every 24 weeks or to 44 μg of subcutaneous interferon beta-1a three times weekly for 96 weeks. Patients had early disease, and a significant proportion was naive to MS treatments.

At 96 weeks, 47.9% and 47.5% of patients receiving ocrelizumab, respectively, had no evidence of disease activity (NEDA) versus 29.2% and 25.1% of patients receiving interferon. NEDA is a composite score defined as the absence of relapses, confirmed disability progression, and new or enlarging T2 or gadolinium-enhancing T1 lesions.

In both studies, relapses occurred in about 20% of patients receiving ocrelizumab versus about 35% of patients receiving interferon. About 10% of participants receiving ocrelizumab and about 15% of patients receiving interferon had clinical disease progression. Similarly, about 10% of patients receiving ocrelizumab developed new gadolinium-enhancing lesions, compared with about 35% of those receiving interferon. New or enlarging T2 lesions were found in about 40% of the ocrelizumab groups and in more than 60% of the interferon groups.

After week 24, 96% of patients receiving ocrelizumab, compared with between 60% and 70% of patients receiving interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new or enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

Ocrelizumab Appears Safe

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment, said investigator Anthony Traboulsee, MD, a neurologist at the University of British Columbia in Vancouver, Canada. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis.” Many patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis because of serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the FDA in the first half of 2016. The FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about four years. Patients had had about 1.5 relapses in the first and second years before entering the studies.

An Alternative to Natalizumab?

The positive results and the increasing buzz about ocrelizumab in the MS community raise the question of how the treatment will fit into the MS armamentarium if it is approved. A review in Therapeutic Advances in Neurological Disorders addressed the issue in January, before the OPERA results were made public.

It’s unclear whether ocrelizumab will become the preferred option when patients have progression on first-line agents such as interferon and glatiramer acetate. Phase II data suggest that ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude, compared with that of fingolimod and natalizumab,” and that the treatment will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favorable risk–benefit profile, compared with natalizumab in [John Cunningham (JC)] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody–positive, whereas natalizumab, or, alternatively, oral fingolimod, would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Per Soelberg Sorensen, MD, and Morten Blinkenberg, MD, PhD, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore postmarketing safety programs will be needed,” they said. The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, eg, every six months [as in OPERA], or if retreatment should be guided by the recovery of CD19-positive B cells.”

 

In any case, infusion reactions with ocrelizumab should be less common than with rituximab, another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody, they concluded.

—M. Alexander Otto

VANCOUVER—Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently reduces relapses, disability progression, and new or enlarging lesions, compared with interferon beta-1a, in patients with relapsing-remitting multiple sclerosis (MS), according to two phase III trials reported at the 68th Annual Meeting of the American Academy of Neurology.

OPERA I and OPERA II

The identical trials, dubbed OPERA I and OPERA II, each included about 800 patients. Subjects were randomized one-to-one to 600 mg of IV ocrelizumab every 24 weeks or to 44 μg of subcutaneous interferon beta-1a three times weekly for 96 weeks. Patients had early disease, and a significant proportion was naive to MS treatments.

At 96 weeks, 47.9% and 47.5% of patients receiving ocrelizumab, respectively, had no evidence of disease activity (NEDA) versus 29.2% and 25.1% of patients receiving interferon. NEDA is a composite score defined as the absence of relapses, confirmed disability progression, and new or enlarging T2 or gadolinium-enhancing T1 lesions.

In both studies, relapses occurred in about 20% of patients receiving ocrelizumab versus about 35% of patients receiving interferon. About 10% of participants receiving ocrelizumab and about 15% of patients receiving interferon had clinical disease progression. Similarly, about 10% of patients receiving ocrelizumab developed new gadolinium-enhancing lesions, compared with about 35% of those receiving interferon. New or enlarging T2 lesions were found in about 40% of the ocrelizumab groups and in more than 60% of the interferon groups.

After week 24, 96% of patients receiving ocrelizumab, compared with between 60% and 70% of patients receiving interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new or enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

Ocrelizumab Appears Safe

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment, said investigator Anthony Traboulsee, MD, a neurologist at the University of British Columbia in Vancouver, Canada. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis.” Many patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis because of serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the FDA in the first half of 2016. The FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about four years. Patients had had about 1.5 relapses in the first and second years before entering the studies.

An Alternative to Natalizumab?

The positive results and the increasing buzz about ocrelizumab in the MS community raise the question of how the treatment will fit into the MS armamentarium if it is approved. A review in Therapeutic Advances in Neurological Disorders addressed the issue in January, before the OPERA results were made public.

It’s unclear whether ocrelizumab will become the preferred option when patients have progression on first-line agents such as interferon and glatiramer acetate. Phase II data suggest that ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude, compared with that of fingolimod and natalizumab,” and that the treatment will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favorable risk–benefit profile, compared with natalizumab in [John Cunningham (JC)] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody–positive, whereas natalizumab, or, alternatively, oral fingolimod, would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Per Soelberg Sorensen, MD, and Morten Blinkenberg, MD, PhD, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore postmarketing safety programs will be needed,” they said. The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, eg, every six months [as in OPERA], or if retreatment should be guided by the recovery of CD19-positive B cells.”

 

In any case, infusion reactions with ocrelizumab should be less common than with rituximab, another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody, they concluded.

—M. Alexander Otto

VANCOUVER—Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently reduces relapses, disability progression, and new or enlarging lesions, compared with interferon beta-1a, in patients with relapsing-remitting multiple sclerosis (MS), according to two phase III trials reported at the 68th Annual Meeting of the American Academy of Neurology.

OPERA I and OPERA II

The identical trials, dubbed OPERA I and OPERA II, each included about 800 patients. Subjects were randomized one-to-one to 600 mg of IV ocrelizumab every 24 weeks or to 44 μg of subcutaneous interferon beta-1a three times weekly for 96 weeks. Patients had early disease, and a significant proportion was naive to MS treatments.

At 96 weeks, 47.9% and 47.5% of patients receiving ocrelizumab, respectively, had no evidence of disease activity (NEDA) versus 29.2% and 25.1% of patients receiving interferon. NEDA is a composite score defined as the absence of relapses, confirmed disability progression, and new or enlarging T2 or gadolinium-enhancing T1 lesions.

In both studies, relapses occurred in about 20% of patients receiving ocrelizumab versus about 35% of patients receiving interferon. About 10% of participants receiving ocrelizumab and about 15% of patients receiving interferon had clinical disease progression. Similarly, about 10% of patients receiving ocrelizumab developed new gadolinium-enhancing lesions, compared with about 35% of those receiving interferon. New or enlarging T2 lesions were found in about 40% of the ocrelizumab groups and in more than 60% of the interferon groups.

After week 24, 96% of patients receiving ocrelizumab, compared with between 60% and 70% of patients receiving interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new or enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

Ocrelizumab Appears Safe

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment, said investigator Anthony Traboulsee, MD, a neurologist at the University of British Columbia in Vancouver, Canada. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis.” Many patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis because of serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the FDA in the first half of 2016. The FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about four years. Patients had had about 1.5 relapses in the first and second years before entering the studies.

An Alternative to Natalizumab?

The positive results and the increasing buzz about ocrelizumab in the MS community raise the question of how the treatment will fit into the MS armamentarium if it is approved. A review in Therapeutic Advances in Neurological Disorders addressed the issue in January, before the OPERA results were made public.

It’s unclear whether ocrelizumab will become the preferred option when patients have progression on first-line agents such as interferon and glatiramer acetate. Phase II data suggest that ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude, compared with that of fingolimod and natalizumab,” and that the treatment will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favorable risk–benefit profile, compared with natalizumab in [John Cunningham (JC)] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody–positive, whereas natalizumab, or, alternatively, oral fingolimod, would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Per Soelberg Sorensen, MD, and Morten Blinkenberg, MD, PhD, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore postmarketing safety programs will be needed,” they said. The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, eg, every six months [as in OPERA], or if retreatment should be guided by the recovery of CD19-positive B cells.”

 

In any case, infusion reactions with ocrelizumab should be less common than with rituximab, another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody, they concluded.

—M. Alexander Otto