MSBoston 2014

AMSTERDAM – An MRI scoring tool helped to identify children with acute central nervous system demyelination who later developed pediatric multiple sclerosis in a prospective study of 284 children.

The tool found that the risk of an MS diagnosis dramatically increased in these children when a baseline MRI showed the presence of one or more T1-weighted hypointense lesions, as well as when scans revealed T2-weighted periventricular lesions.

"Several studies have described the MRI characteristics of pediatric patients with established MS, and how they compare to that of adults matched for disease duration," said Leonard Verhey, a doctoral student working with Dr. Brenda Banwell at the Hospital for Sick Children at the University of Toronto.

"However, less is known about the MRI features that predict MS in children with acute demyelination, and how these features might compare with the predictive criteria for adult-onset MS."

Mr. Verhey and his associates used a standardized 14-item MRI scoring tool to identify MRI parameters that might predict MS in an unselected population of children with acute CNS demyelination. The tool was originally developed based on data from 61 children with relapsing-remitting MS (RRMS), monophasic acute disseminated encephalomyelitis, and non-demyelinating CNS inflammation, none of whom were included in the current prospective study.

The investigators recruited children younger than 16 years for the current study at 23 centers in Canada. During a 5-year follow-up period, they obtained MRI scans at baseline, 3 months, 6 months, and 1 year. The study’s funding did not allow serial MRIs to be taken between years 2 and 5 of follow-up, but the children were assessed clinically every year until the end of the study, and some had additional MRIs taken if required.

"Less is known about the MRI features that predict MS in children with acute demyelination."

Two experts, blinded to the clinical findings, scored all MRI scans with the standardized 14-item tool. So far, 57 (20%) children have been given a confirmed diagnosis of MS, while the remainder (n = 227) have monophasic acute acquired demyelination (ADS). Those with MS had been followed for a mean of 4.3 years, while those with monophasic ADS had been observed for a mean of 3.9 years, Mr. Verhey reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Patients with pediatric MS were significantly more likely than were those with monophasic ADS to have an older age of onset (12.8 vs. 8.8 years) and to be female (67% vs. 48%).

The most common abnormality seen on baseline MRI was the presence of T2-weighted lesions (about 60% of the entire cohort). Other lesions affected the brainstem, periventricular area, or cerebral white matter in about 40% of patients. T1 hypointense lesions also were seen in about 30% of scans.

A univariate analysis identified nine MRI characteristics that were indicative of an MS diagnosis. "T1 hypointense lesions showed the strongest association with MS outcome," noted Mr. Verhey, who won one of the two best oral presentation awards given to young investigators at the congress.

Periventricular lesions also were strongly associated with outcome, and "interestingly, although only 22% of the patients had contrast-enhancing lesions, this was still associated with a 10-fold increased risk of MS diagnosis," he said. Another interesting finding was that the presence of thalamic lesions appeared to confer a 61% decreased risk of MS diagnosis.

A multivariate analysis that adjusted for age and gender revealed only two significant and independent predictors of an MS diagnosis: the presence of one or more T1 hypointense lesions (hazard ratio, 20.3), which were found in scans of 80 (28%) patients; and one or more T2 periventricular lesions, which occurred in scans of 112 (39%) patients (HR, 3.3). If both of these parameters were present at baseline, the risk of MS diagnosis was greatly increased (HR, 34.3).

Mr. Verhey and his colleagues found that those two predictive factors had a more favorable combination of sensitivity (84%), specificity (93%), positive-predictive value (76%), and negative-predictive value (96%) than did other predictive models in published studies.

Another 100 children will be enrolled in a validation cohort. Other centers may be able to validate the results because of the tool’s high inter-rater reliability and its accompanying MRI atlas, he said.

Mr. Verhey noted that the study has been accepted for publication in the Lancet Neurology.

The study was supported by a grant from the Multiple Sclerosis Scientific Research Foundation. Additional support was provided by the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, and the Hospital for Sick Children. None of the investigators had relevant disclosures.

AMSTERDAM – An MRI scoring tool helped to identify children with acute central nervous system demyelination who later developed pediatric multiple sclerosis in a prospective study of 284 children.

The tool found that the risk of an MS diagnosis dramatically increased in these children when a baseline MRI showed the presence of one or more T1-weighted hypointense lesions, as well as when scans revealed T2-weighted periventricular lesions.

"Several studies have described the MRI characteristics of pediatric patients with established MS, and how they compare to that of adults matched for disease duration," said Leonard Verhey, a doctoral student working with Dr. Brenda Banwell at the Hospital for Sick Children at the University of Toronto.

"However, less is known about the MRI features that predict MS in children with acute demyelination, and how these features might compare with the predictive criteria for adult-onset MS."

Mr. Verhey and his associates used a standardized 14-item MRI scoring tool to identify MRI parameters that might predict MS in an unselected population of children with acute CNS demyelination. The tool was originally developed based on data from 61 children with relapsing-remitting MS (RRMS), monophasic acute disseminated encephalomyelitis, and non-demyelinating CNS inflammation, none of whom were included in the current prospective study.

The investigators recruited children younger than 16 years for the current study at 23 centers in Canada. During a 5-year follow-up period, they obtained MRI scans at baseline, 3 months, 6 months, and 1 year. The study’s funding did not allow serial MRIs to be taken between years 2 and 5 of follow-up, but the children were assessed clinically every year until the end of the study, and some had additional MRIs taken if required.

"Less is known about the MRI features that predict MS in children with acute demyelination."

Two experts, blinded to the clinical findings, scored all MRI scans with the standardized 14-item tool. So far, 57 (20%) children have been given a confirmed diagnosis of MS, while the remainder (n = 227) have monophasic acute acquired demyelination (ADS). Those with MS had been followed for a mean of 4.3 years, while those with monophasic ADS had been observed for a mean of 3.9 years, Mr. Verhey reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Patients with pediatric MS were significantly more likely than were those with monophasic ADS to have an older age of onset (12.8 vs. 8.8 years) and to be female (67% vs. 48%).

The most common abnormality seen on baseline MRI was the presence of T2-weighted lesions (about 60% of the entire cohort). Other lesions affected the brainstem, periventricular area, or cerebral white matter in about 40% of patients. T1 hypointense lesions also were seen in about 30% of scans.

A univariate analysis identified nine MRI characteristics that were indicative of an MS diagnosis. "T1 hypointense lesions showed the strongest association with MS outcome," noted Mr. Verhey, who won one of the two best oral presentation awards given to young investigators at the congress.

Periventricular lesions also were strongly associated with outcome, and "interestingly, although only 22% of the patients had contrast-enhancing lesions, this was still associated with a 10-fold increased risk of MS diagnosis," he said. Another interesting finding was that the presence of thalamic lesions appeared to confer a 61% decreased risk of MS diagnosis.

A multivariate analysis that adjusted for age and gender revealed only two significant and independent predictors of an MS diagnosis: the presence of one or more T1 hypointense lesions (hazard ratio, 20.3), which were found in scans of 80 (28%) patients; and one or more T2 periventricular lesions, which occurred in scans of 112 (39%) patients (HR, 3.3). If both of these parameters were present at baseline, the risk of MS diagnosis was greatly increased (HR, 34.3).

Mr. Verhey and his colleagues found that those two predictive factors had a more favorable combination of sensitivity (84%), specificity (93%), positive-predictive value (76%), and negative-predictive value (96%) than did other predictive models in published studies.

Another 100 children will be enrolled in a validation cohort. Other centers may be able to validate the results because of the tool’s high inter-rater reliability and its accompanying MRI atlas, he said.

Mr. Verhey noted that the study has been accepted for publication in the Lancet Neurology.

The study was supported by a grant from the Multiple Sclerosis Scientific Research Foundation. Additional support was provided by the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, and the Hospital for Sick Children. None of the investigators had relevant disclosures.

AMSTERDAM – An MRI scoring tool helped to identify children with acute central nervous system demyelination who later developed pediatric multiple sclerosis in a prospective study of 284 children.

The tool found that the risk of an MS diagnosis dramatically increased in these children when a baseline MRI showed the presence of one or more T1-weighted hypointense lesions, as well as when scans revealed T2-weighted periventricular lesions.

"Several studies have described the MRI characteristics of pediatric patients with established MS, and how they compare to that of adults matched for disease duration," said Leonard Verhey, a doctoral student working with Dr. Brenda Banwell at the Hospital for Sick Children at the University of Toronto.

"However, less is known about the MRI features that predict MS in children with acute demyelination, and how these features might compare with the predictive criteria for adult-onset MS."

Mr. Verhey and his associates used a standardized 14-item MRI scoring tool to identify MRI parameters that might predict MS in an unselected population of children with acute CNS demyelination. The tool was originally developed based on data from 61 children with relapsing-remitting MS (RRMS), monophasic acute disseminated encephalomyelitis, and non-demyelinating CNS inflammation, none of whom were included in the current prospective study.

The investigators recruited children younger than 16 years for the current study at 23 centers in Canada. During a 5-year follow-up period, they obtained MRI scans at baseline, 3 months, 6 months, and 1 year. The study’s funding did not allow serial MRIs to be taken between years 2 and 5 of follow-up, but the children were assessed clinically every year until the end of the study, and some had additional MRIs taken if required.

"Less is known about the MRI features that predict MS in children with acute demyelination."

Two experts, blinded to the clinical findings, scored all MRI scans with the standardized 14-item tool. So far, 57 (20%) children have been given a confirmed diagnosis of MS, while the remainder (n = 227) have monophasic acute acquired demyelination (ADS). Those with MS had been followed for a mean of 4.3 years, while those with monophasic ADS had been observed for a mean of 3.9 years, Mr. Verhey reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Patients with pediatric MS were significantly more likely than were those with monophasic ADS to have an older age of onset (12.8 vs. 8.8 years) and to be female (67% vs. 48%).

The most common abnormality seen on baseline MRI was the presence of T2-weighted lesions (about 60% of the entire cohort). Other lesions affected the brainstem, periventricular area, or cerebral white matter in about 40% of patients. T1 hypointense lesions also were seen in about 30% of scans.

A univariate analysis identified nine MRI characteristics that were indicative of an MS diagnosis. "T1 hypointense lesions showed the strongest association with MS outcome," noted Mr. Verhey, who won one of the two best oral presentation awards given to young investigators at the congress.

Periventricular lesions also were strongly associated with outcome, and "interestingly, although only 22% of the patients had contrast-enhancing lesions, this was still associated with a 10-fold increased risk of MS diagnosis," he said. Another interesting finding was that the presence of thalamic lesions appeared to confer a 61% decreased risk of MS diagnosis.

A multivariate analysis that adjusted for age and gender revealed only two significant and independent predictors of an MS diagnosis: the presence of one or more T1 hypointense lesions (hazard ratio, 20.3), which were found in scans of 80 (28%) patients; and one or more T2 periventricular lesions, which occurred in scans of 112 (39%) patients (HR, 3.3). If both of these parameters were present at baseline, the risk of MS diagnosis was greatly increased (HR, 34.3).

Mr. Verhey and his colleagues found that those two predictive factors had a more favorable combination of sensitivity (84%), specificity (93%), positive-predictive value (76%), and negative-predictive value (96%) than did other predictive models in published studies.

Another 100 children will be enrolled in a validation cohort. Other centers may be able to validate the results because of the tool’s high inter-rater reliability and its accompanying MRI atlas, he said.

Mr. Verhey noted that the study has been accepted for publication in the Lancet Neurology.

The study was supported by a grant from the Multiple Sclerosis Scientific Research Foundation. Additional support was provided by the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, and the Hospital for Sick Children. None of the investigators had relevant disclosures.

AMSTERDAM – Progression from clinically isolated syndrome to clinically definite multiple sclerosis in patients who do not receive early disease-modifying treatment can be predicted by several features on brain MRI and oligoclonal band positivity, according to findings from the MSBase Registry.

Only one factor – the presence of one or more gadolinium-enhancing (GdE) T1 lesions – was a significant predictor of clinically definite MS (CDMS) in patients who received early disease-modifying therapy (DMT) after experiencing clinically isolated syndrome (CIS), Dr. Claire Meyniel reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

"When facing a patient with CIS, the main point is to know whether or not he or she will develop clinically defined MS," said Dr. Meyniel of the neurology department at the University Hospital Nantes (France).

Predicting which patients with CIS will progress to CDMS has often been difficult, but progress in the diagnosis of MS with MRI during the past 10 years, including recently revised McDonald criteria (Ann. Neurol. 2011;69:292-302), have simplified diagnostic criteria for MS without compromising their specificity, she said.

To determine how these criteria performed in "real-world" clinical practice in the prediction of a second event in patients with CIS, Dr. Meyniel and her coauthors in the MSBase Incident Study obtained the records of 1,266 patients with CIS who had been diagnosed by a neurologist within 12 months of presentation and received at least annual follow-up. The investigators also wanted to find signals that could help to guide clinicians in identifying patients with CIS who might be at higher risk than others for developing CDMS.

MSBase is an online registry containing the records of more than 18,400 patients with MS who are being treated at 59 centers in 17 countries. The registry is run by the MSBase Foundation, a not-for-profit organization located in the Royal Melbourne Hospital in Australia.

The mean age of CIS onset in the patients (71% female) was 32.5 years. Overall, 88% had undergone GdE brain MRI, 50% had undergone lumbar puncture, and 55% had received spinal MRI. Of the 1,266 patients, 292 (23%) had received DMT.

After a mean follow up of 2.7 years, 698 (55%) of patients with CIS had a first relapse and fulfilled criteria for CDMS. The hazard ratio (HR) for conversion to CDMS was 3.02 for patients who had not received DMT, compared with those who had. Receipt of DMT also significantly extended the mean time to first relapse in comparison with no treatment (1.14 years vs. 0.44 years).

The independent predictors of CDMS in multivariate Cox proportional hazards regression analyses of the 974 patients who had not received DMT, included having three or more T2 lesions (HR, 1.41), one or more infratentorial lesions (HR, 1.25), one or more juxtacortical lesions (HR, 1.25), and being oligoclonal band (OCB) positive (HR, 1.47).

In DMT-treated patients, the only independent predictive factor for CIS progression to CDMS was the presence of one or more GdE T1 lesions (HR, 1.66).

"This study underlines the value of early treatment to prolong time to a second event in CIS patients," Dr. Meyniel said, adding that it also identified several MRI predictors that can help determine progression to CDMS.

"This is an interesting project, especially since this is showing ‘real-world’ applicability of criteria and recommendations," said Dr. Heinz Wiendl of the University of Münster (Germany), who was one of the session moderators.

Another session moderator, Dr. Henry F. McFarland, chief of the Neuroimmunology Branch at the National Institute for Neurological Disorders and Stroke, said in an interview that predicting which patients will develop MS or respond to treatment was a challenge for the physician.

"The bottom line is that MRI is probably the best predictor of patients not responding to treatment," he said.

The MSBase Foundation receives financial support in the form of grants from Merck Serono, Biogen Idec, Novartis Pharma, Bayer Schering Pharma, and Sanofi-Aventis. Dr. Meyniel had no personal conflicts of interest to disclose. Dr. Wiendl and Dr. McFarland had no conflicts of interest relevant to the study.

AMSTERDAM – Progression from clinically isolated syndrome to clinically definite multiple sclerosis in patients who do not receive early disease-modifying treatment can be predicted by several features on brain MRI and oligoclonal band positivity, according to findings from the MSBase Registry.

Only one factor – the presence of one or more gadolinium-enhancing (GdE) T1 lesions – was a significant predictor of clinically definite MS (CDMS) in patients who received early disease-modifying therapy (DMT) after experiencing clinically isolated syndrome (CIS), Dr. Claire Meyniel reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

"When facing a patient with CIS, the main point is to know whether or not he or she will develop clinically defined MS," said Dr. Meyniel of the neurology department at the University Hospital Nantes (France).

Predicting which patients with CIS will progress to CDMS has often been difficult, but progress in the diagnosis of MS with MRI during the past 10 years, including recently revised McDonald criteria (Ann. Neurol. 2011;69:292-302), have simplified diagnostic criteria for MS without compromising their specificity, she said.

To determine how these criteria performed in "real-world" clinical practice in the prediction of a second event in patients with CIS, Dr. Meyniel and her coauthors in the MSBase Incident Study obtained the records of 1,266 patients with CIS who had been diagnosed by a neurologist within 12 months of presentation and received at least annual follow-up. The investigators also wanted to find signals that could help to guide clinicians in identifying patients with CIS who might be at higher risk than others for developing CDMS.

MSBase is an online registry containing the records of more than 18,400 patients with MS who are being treated at 59 centers in 17 countries. The registry is run by the MSBase Foundation, a not-for-profit organization located in the Royal Melbourne Hospital in Australia.

The mean age of CIS onset in the patients (71% female) was 32.5 years. Overall, 88% had undergone GdE brain MRI, 50% had undergone lumbar puncture, and 55% had received spinal MRI. Of the 1,266 patients, 292 (23%) had received DMT.

After a mean follow up of 2.7 years, 698 (55%) of patients with CIS had a first relapse and fulfilled criteria for CDMS. The hazard ratio (HR) for conversion to CDMS was 3.02 for patients who had not received DMT, compared with those who had. Receipt of DMT also significantly extended the mean time to first relapse in comparison with no treatment (1.14 years vs. 0.44 years).

The independent predictors of CDMS in multivariate Cox proportional hazards regression analyses of the 974 patients who had not received DMT, included having three or more T2 lesions (HR, 1.41), one or more infratentorial lesions (HR, 1.25), one or more juxtacortical lesions (HR, 1.25), and being oligoclonal band (OCB) positive (HR, 1.47).

In DMT-treated patients, the only independent predictive factor for CIS progression to CDMS was the presence of one or more GdE T1 lesions (HR, 1.66).

"This study underlines the value of early treatment to prolong time to a second event in CIS patients," Dr. Meyniel said, adding that it also identified several MRI predictors that can help determine progression to CDMS.

"This is an interesting project, especially since this is showing ‘real-world’ applicability of criteria and recommendations," said Dr. Heinz Wiendl of the University of Münster (Germany), who was one of the session moderators.

Another session moderator, Dr. Henry F. McFarland, chief of the Neuroimmunology Branch at the National Institute for Neurological Disorders and Stroke, said in an interview that predicting which patients will develop MS or respond to treatment was a challenge for the physician.

"The bottom line is that MRI is probably the best predictor of patients not responding to treatment," he said.

The MSBase Foundation receives financial support in the form of grants from Merck Serono, Biogen Idec, Novartis Pharma, Bayer Schering Pharma, and Sanofi-Aventis. Dr. Meyniel had no personal conflicts of interest to disclose. Dr. Wiendl and Dr. McFarland had no conflicts of interest relevant to the study.

AMSTERDAM – Progression from clinically isolated syndrome to clinically definite multiple sclerosis in patients who do not receive early disease-modifying treatment can be predicted by several features on brain MRI and oligoclonal band positivity, according to findings from the MSBase Registry.

Only one factor – the presence of one or more gadolinium-enhancing (GdE) T1 lesions – was a significant predictor of clinically definite MS (CDMS) in patients who received early disease-modifying therapy (DMT) after experiencing clinically isolated syndrome (CIS), Dr. Claire Meyniel reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

"When facing a patient with CIS, the main point is to know whether or not he or she will develop clinically defined MS," said Dr. Meyniel of the neurology department at the University Hospital Nantes (France).

Predicting which patients with CIS will progress to CDMS has often been difficult, but progress in the diagnosis of MS with MRI during the past 10 years, including recently revised McDonald criteria (Ann. Neurol. 2011;69:292-302), have simplified diagnostic criteria for MS without compromising their specificity, she said.

To determine how these criteria performed in "real-world" clinical practice in the prediction of a second event in patients with CIS, Dr. Meyniel and her coauthors in the MSBase Incident Study obtained the records of 1,266 patients with CIS who had been diagnosed by a neurologist within 12 months of presentation and received at least annual follow-up. The investigators also wanted to find signals that could help to guide clinicians in identifying patients with CIS who might be at higher risk than others for developing CDMS.

MSBase is an online registry containing the records of more than 18,400 patients with MS who are being treated at 59 centers in 17 countries. The registry is run by the MSBase Foundation, a not-for-profit organization located in the Royal Melbourne Hospital in Australia.

The mean age of CIS onset in the patients (71% female) was 32.5 years. Overall, 88% had undergone GdE brain MRI, 50% had undergone lumbar puncture, and 55% had received spinal MRI. Of the 1,266 patients, 292 (23%) had received DMT.

After a mean follow up of 2.7 years, 698 (55%) of patients with CIS had a first relapse and fulfilled criteria for CDMS. The hazard ratio (HR) for conversion to CDMS was 3.02 for patients who had not received DMT, compared with those who had. Receipt of DMT also significantly extended the mean time to first relapse in comparison with no treatment (1.14 years vs. 0.44 years).

The independent predictors of CDMS in multivariate Cox proportional hazards regression analyses of the 974 patients who had not received DMT, included having three or more T2 lesions (HR, 1.41), one or more infratentorial lesions (HR, 1.25), one or more juxtacortical lesions (HR, 1.25), and being oligoclonal band (OCB) positive (HR, 1.47).

In DMT-treated patients, the only independent predictive factor for CIS progression to CDMS was the presence of one or more GdE T1 lesions (HR, 1.66).

"This study underlines the value of early treatment to prolong time to a second event in CIS patients," Dr. Meyniel said, adding that it also identified several MRI predictors that can help determine progression to CDMS.

"This is an interesting project, especially since this is showing ‘real-world’ applicability of criteria and recommendations," said Dr. Heinz Wiendl of the University of Münster (Germany), who was one of the session moderators.

Another session moderator, Dr. Henry F. McFarland, chief of the Neuroimmunology Branch at the National Institute for Neurological Disorders and Stroke, said in an interview that predicting which patients will develop MS or respond to treatment was a challenge for the physician.

"The bottom line is that MRI is probably the best predictor of patients not responding to treatment," he said.

The MSBase Foundation receives financial support in the form of grants from Merck Serono, Biogen Idec, Novartis Pharma, Bayer Schering Pharma, and Sanofi-Aventis. Dr. Meyniel had no personal conflicts of interest to disclose. Dr. Wiendl and Dr. McFarland had no conflicts of interest relevant to the study.

AMSTERDAM – MRI of the brain performed 1 year after starting disease-modifying treatment for relapsing-remitting multiple sclerosis predicted response to treatment at 5 years in a retrospective, observational, single-center study.

Several other baseline predictors of a better response to disease-modifying treatment (DMT) at 5 years included male sex, a low EDSS (Expanded Disability Status Scale) score, the presence of monofocal disease, and fewer gadolinium-enhancing (GdE) T1-weighted lesions on MRI.

Previous studies have found that MRI performed 1 year after initiation of DMT can predict treatment response in the subsequent 2-3 years (Eur. J. Neurol. 2009;16:1202-9; Mult. Scler. 2009;15:848-53). But Dr. Marzia Romeo, the lead investigator of the current study, and her colleagues sought to determine if it could also predict longer-term outcomes.

"One of our many issues is to identify patients who benefit from first-line therapy for MS," said Dr. Romeo of the San Raffaele Hospital in Milan at the joint triennial congressof the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

The investigators selected 668 patients with relapsing-remitting multiple sclerosis (RRMS) who started treatment with a first-line DMT (interferon beta-1a or glatiramer acetate [Copaxone]) in 1996-2005 and had at least 5 years of follow-up data available. Of the 668 patients who were eligible, 398 (60%) had undergone MRI after 1 year of therapy.

The mean ages for MS onset and the start of first-line DMT were 28.9 years and 34.5 years, respectively. The majority of patients in the cohort (77%) were women.

"One of our many issues is to identify patients who benefit from first-line therapy for MS."

After 5 years of treatment, Dr. Romeo and her associates classified 33% of patients as full responders, 22% as partial responders, and the remaining 45% as nonresponders. They defined treatment response according to the following clinical criteria:

• Full response. The patient had no sign of clinical relapse, and there was less than a 1.5-point increase in the EDSS score.

• Partial response. The patient experienced one or more relapses but had an EDSS score increase of 1.5 points or less.

• Nonresponse. The EDSS score increased by 1.5 points or more starting at 6 months after initiation of DMT, and persisted up to the 5-year follow-up examination, or the use of a second-line therapy.

Slightly more than half (51%) of the study population were treated with the same DMT throughout the 5-year evaluation period. Another 37% switched to an alternative DMT, and 12% switched to a second-line therapy.

Dr. Romeo reported that 78% of full responders remained on the same DMT that they started at the beginning of treatment, compared with only 17% of nonresponders.

The presence of more than two GdE T1 lesions at 1 year was associated with nearly sixfold greater odds for nonresponse to DMT at 5 years in a comparison of full- and nonresponders (P less than .0001).

At baseline, full responders were significantly more likely than nonresponders to be male (75% vs. 65%) and to have a lower EDSS score (mean, 1.6 vs. 2.1), a lower prevalence of multifocal disease (21% vs. 30%), and a lower prevalence of two or more GdE T1 lesions (18% vs. 32%). Dr. Romeo noted that patients with these characteristics at baseline should be considered for induction therapy.

"In the subgroup of patients in whom we performed MRI after 1 year of treatment, we observed that the patients with more than two active lesions were nonresponders and had a high risk of disability progression after the 5 years’ follow-up," she said. An alternative treatment should be considered in these patients with active lesions (defined as a new T2 or GdE T1 lesions, "before irreversible neurological disability occurs."

Dr. Romero reported having no conflicts of interest. Several of her coauthors disclosed receiving research grants or receiving honoraria for speaking, consulting, or participating on an advisory board for Actelion, Bayer Schering Pharma, Biogen-Dompé SG (and Biogen Idec), Merck Serono, Novartis, Sanofi-Aventis, Serono Symposia International Foundation, Synthon, and Teva Pharmaceuticals.

AMSTERDAM – MRI of the brain performed 1 year after starting disease-modifying treatment for relapsing-remitting multiple sclerosis predicted response to treatment at 5 years in a retrospective, observational, single-center study.

Several other baseline predictors of a better response to disease-modifying treatment (DMT) at 5 years included male sex, a low EDSS (Expanded Disability Status Scale) score, the presence of monofocal disease, and fewer gadolinium-enhancing (GdE) T1-weighted lesions on MRI.

Previous studies have found that MRI performed 1 year after initiation of DMT can predict treatment response in the subsequent 2-3 years (Eur. J. Neurol. 2009;16:1202-9; Mult. Scler. 2009;15:848-53). But Dr. Marzia Romeo, the lead investigator of the current study, and her colleagues sought to determine if it could also predict longer-term outcomes.

"One of our many issues is to identify patients who benefit from first-line therapy for MS," said Dr. Romeo of the San Raffaele Hospital in Milan at the joint triennial congressof the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

The investigators selected 668 patients with relapsing-remitting multiple sclerosis (RRMS) who started treatment with a first-line DMT (interferon beta-1a or glatiramer acetate [Copaxone]) in 1996-2005 and had at least 5 years of follow-up data available. Of the 668 patients who were eligible, 398 (60%) had undergone MRI after 1 year of therapy.

The mean ages for MS onset and the start of first-line DMT were 28.9 years and 34.5 years, respectively. The majority of patients in the cohort (77%) were women.

"One of our many issues is to identify patients who benefit from first-line therapy for MS."

After 5 years of treatment, Dr. Romeo and her associates classified 33% of patients as full responders, 22% as partial responders, and the remaining 45% as nonresponders. They defined treatment response according to the following clinical criteria:

• Full response. The patient had no sign of clinical relapse, and there was less than a 1.5-point increase in the EDSS score.

• Partial response. The patient experienced one or more relapses but had an EDSS score increase of 1.5 points or less.

• Nonresponse. The EDSS score increased by 1.5 points or more starting at 6 months after initiation of DMT, and persisted up to the 5-year follow-up examination, or the use of a second-line therapy.

Slightly more than half (51%) of the study population were treated with the same DMT throughout the 5-year evaluation period. Another 37% switched to an alternative DMT, and 12% switched to a second-line therapy.

Dr. Romeo reported that 78% of full responders remained on the same DMT that they started at the beginning of treatment, compared with only 17% of nonresponders.

The presence of more than two GdE T1 lesions at 1 year was associated with nearly sixfold greater odds for nonresponse to DMT at 5 years in a comparison of full- and nonresponders (P less than .0001).

At baseline, full responders were significantly more likely than nonresponders to be male (75% vs. 65%) and to have a lower EDSS score (mean, 1.6 vs. 2.1), a lower prevalence of multifocal disease (21% vs. 30%), and a lower prevalence of two or more GdE T1 lesions (18% vs. 32%). Dr. Romeo noted that patients with these characteristics at baseline should be considered for induction therapy.

"In the subgroup of patients in whom we performed MRI after 1 year of treatment, we observed that the patients with more than two active lesions were nonresponders and had a high risk of disability progression after the 5 years’ follow-up," she said. An alternative treatment should be considered in these patients with active lesions (defined as a new T2 or GdE T1 lesions, "before irreversible neurological disability occurs."

Dr. Romero reported having no conflicts of interest. Several of her coauthors disclosed receiving research grants or receiving honoraria for speaking, consulting, or participating on an advisory board for Actelion, Bayer Schering Pharma, Biogen-Dompé SG (and Biogen Idec), Merck Serono, Novartis, Sanofi-Aventis, Serono Symposia International Foundation, Synthon, and Teva Pharmaceuticals.

AMSTERDAM – MRI of the brain performed 1 year after starting disease-modifying treatment for relapsing-remitting multiple sclerosis predicted response to treatment at 5 years in a retrospective, observational, single-center study.

Several other baseline predictors of a better response to disease-modifying treatment (DMT) at 5 years included male sex, a low EDSS (Expanded Disability Status Scale) score, the presence of monofocal disease, and fewer gadolinium-enhancing (GdE) T1-weighted lesions on MRI.

Previous studies have found that MRI performed 1 year after initiation of DMT can predict treatment response in the subsequent 2-3 years (Eur. J. Neurol. 2009;16:1202-9; Mult. Scler. 2009;15:848-53). But Dr. Marzia Romeo, the lead investigator of the current study, and her colleagues sought to determine if it could also predict longer-term outcomes.

"One of our many issues is to identify patients who benefit from first-line therapy for MS," said Dr. Romeo of the San Raffaele Hospital in Milan at the joint triennial congressof the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

The investigators selected 668 patients with relapsing-remitting multiple sclerosis (RRMS) who started treatment with a first-line DMT (interferon beta-1a or glatiramer acetate [Copaxone]) in 1996-2005 and had at least 5 years of follow-up data available. Of the 668 patients who were eligible, 398 (60%) had undergone MRI after 1 year of therapy.

The mean ages for MS onset and the start of first-line DMT were 28.9 years and 34.5 years, respectively. The majority of patients in the cohort (77%) were women.

"One of our many issues is to identify patients who benefit from first-line therapy for MS."

After 5 years of treatment, Dr. Romeo and her associates classified 33% of patients as full responders, 22% as partial responders, and the remaining 45% as nonresponders. They defined treatment response according to the following clinical criteria:

• Full response. The patient had no sign of clinical relapse, and there was less than a 1.5-point increase in the EDSS score.

• Partial response. The patient experienced one or more relapses but had an EDSS score increase of 1.5 points or less.

• Nonresponse. The EDSS score increased by 1.5 points or more starting at 6 months after initiation of DMT, and persisted up to the 5-year follow-up examination, or the use of a second-line therapy.

Slightly more than half (51%) of the study population were treated with the same DMT throughout the 5-year evaluation period. Another 37% switched to an alternative DMT, and 12% switched to a second-line therapy.

Dr. Romeo reported that 78% of full responders remained on the same DMT that they started at the beginning of treatment, compared with only 17% of nonresponders.

The presence of more than two GdE T1 lesions at 1 year was associated with nearly sixfold greater odds for nonresponse to DMT at 5 years in a comparison of full- and nonresponders (P less than .0001).

At baseline, full responders were significantly more likely than nonresponders to be male (75% vs. 65%) and to have a lower EDSS score (mean, 1.6 vs. 2.1), a lower prevalence of multifocal disease (21% vs. 30%), and a lower prevalence of two or more GdE T1 lesions (18% vs. 32%). Dr. Romeo noted that patients with these characteristics at baseline should be considered for induction therapy.

"In the subgroup of patients in whom we performed MRI after 1 year of treatment, we observed that the patients with more than two active lesions were nonresponders and had a high risk of disability progression after the 5 years’ follow-up," she said. An alternative treatment should be considered in these patients with active lesions (defined as a new T2 or GdE T1 lesions, "before irreversible neurological disability occurs."

Dr. Romero reported having no conflicts of interest. Several of her coauthors disclosed receiving research grants or receiving honoraria for speaking, consulting, or participating on an advisory board for Actelion, Bayer Schering Pharma, Biogen-Dompé SG (and Biogen Idec), Merck Serono, Novartis, Sanofi-Aventis, Serono Symposia International Foundation, Synthon, and Teva Pharmaceuticals.

AMSTERDAM – While the B-cell targeted drug atacicept failed to improve disease activity in patients with relapsing remitting multiple sclerosis and even may have made the patients’ conditions worse, another anti–B-cell drug, ocrelizumab, is showing positive signs of being a future treatment for the disease.

Even though atacicept decreased mature B-cell proliferation and levels of serum immunoglobulins in the ATAMS (Atacicept in Multiple Sclerosis) randomized, phase II study – as would have been expected – patients who received atacicept had a higher annualized relapse rate (ARR) and more gadolinium-enhancing (GdE) lesions than did those on placebo. Atacicept is a recombinant fusion protein containing the soluble TACI receptor. It binds to and neutralizes the B-cell stimulatory cytokines B-Lymphocyte Stimulator and A Proliferation-Inducing Ligand and also blocks the activation of TACI receptors on mature B cells.

Data from a separate multicenter, randomized trial with ocrelizumab appear in stark contrast to the ATAMS study, as ocrelizumab clearly had a beneficial effect on the number of GdE lesions and ARR, and the findings appear to persist in the long term. Ocrelizumab is a humanized monoclonal antibody that targets CD-20 on the surface of B cells, much like rituximab (Rituxan), which has also been investigated as a potential MS therapy.

At the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), where the ATAMS results were presented, Dr. Ralf Gold of St. Josef Hospital and St. Elisabeth Hospital, both in Bochum, Germany, commented that the ATAMS findings came as a surprise because multiple studies have indicated a clear rationale for targeting B cells in MS.

"B cells have regulatory capacities [and] it may be that [with atacicept] you may impair regulatory pathways rather than silence the active and putative pathogenic B cells," Dr. Gold suggested. "Our immune system is very selective," he said, adding that there may be other explanations that would no doubt be discussed when the ATAMS data are published.

"B cells play a multifaceted role in the immune system and ... there can be unintended consequences for a therapy based on our incomplete understanding of B-cell biology," said Timothy Coetzee, Ph.D., the chief research officer of the National MS Society in the United States.

Dr. Coetzee, who was not involved in either study, noted in an interview that the ATAMS findings in particular highlight the complexity of B-cell signaling in MS.

"Although there is much we know about B cells, our understanding of these cells continues to evolve as we discover that they have new and unexpected roles to play." he said. "I suspect that that is what we saw with ATAMS. This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

"B cells play a multifaceted role in the immune system."

In ATAMS, the ARR for atacicept after 36 weeks was 0.86 with the 25-mg dose, 0.79 with the 75-mg dose, and 0.96 with the 150-mg dose, compared with 0.38 for placebo. In addition, patients who were given the experimental drug showed evidence of more, not fewer, GdE T1 lesions on MRI, which was the study’s primary end point.

The ATAMS study was halted early, in September 2009, after an independent data safety monitoring board identified these negative findings, Dr. Ludwig Kappos, chair of neurology at the University Hospital Basel (Switzerland), said at the congress.

Speaking on behalf of the ATAMS study group, Dr. Kappos noted that the apparently detrimental effects of atacicept appear to be reversed in the long term once treatment has stopped. The ATAMS trial protocol was amended to allow all patients who had been randomized into the trial to participate in an extended follow-up study for safety.

Of 255 patients who were enrolled in the trial, 184 underwent an extended 60-week evaluation. During this time, the mean ARR seen with two of the three doses of atacicept fell to rates similar to placebo, at 0.25 for the 25-mg dose (P less than .001 vs. placebo) and 0.29 for the 75-mg dose (P equals .014 vs. placebo), and 0.27 for placebo. The ARR for the 150-mg dose was 0.45.

"At least it was reassuring to observe that the negative effect that we might have had with this agent was reversed and did not persist over the end of treatment period," Dr. Kappos said.

He noted that at baseline there were higher percentages of patients in the atacicept groups who had no signs of GdE T1 lesions than there were in patients who received placebo (61.5% to 68.3% vs. 54%). There also was prior to treatment a higher mean number of GdE T1 lesions in placebo-treated patients, compared with patients who received atacicept at a dose of 25 mg or 75 mg (4.1 vs. 2.1 and 3.7, respectively). There were 4.7 GdE T1 lesions at baseline in patients treated with 150 mg.

Whether this slight imbalance in baseline characteristics or the manner in which atacicept targets B cells had any effect on the study’s outcomes remains to be seen, Dr. Kappos said.

In the other phase II trial, 220 patients with relapsing remitting MS who were randomized to receive two cycles of ocrelizumab for a total infusion dose of 600 mg or 2,000 mg, given in two divided doses of 300 mg or 1,000 mg, respectively, separated by 14 days. Other patients were given matching placebo infusions or open-label (rater-blinded) intramuscular interferon beta-1a (IFNB-1a, Avonex) 30 mcg once weekly.

Ocrelizumab not only significantly reduced the ARR by 73%-80%, but also reduced the mean number of GdE T1 lesions by 86%-96% versus placebo (P less than .0001). The ARRs for ocrelizumab at 24 weeks were significantly reduced with 600 mg and 2,000 mg ocrelizumab, compared with placebo, and, in an exploratory analysis, with IFNB-1a. The ARRs were 0.13 for the 600-mg dose and 0.17 for the 2,000-mg dose, compared with 0.64 for placebo and 0.36 for IFNB-1a, reported Dr. Kappos, who also was lead author on this study (Lancet 2011 Nov. 1 [doi:10.1016/S0140-6736(11)61649-8]).

"This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

The mean total number of GdE T1 lesions over weeks 12, 16, 20, and 24 was 0.8 for both 600 mg and 2,000 mg ocrelizumab, which was significantly different from the mean of 6.6 lesions observed in the placebo group.

The study shows "the effectiveness of B cell depletion with both ocrelizumab doses ... with favorable short-term safety profile," according to the study authors. Dr. Kappos also recently presented long-term data from the trial in a poster at the congress.

After week 24, all 183 patients who continued to participate in the 96-week extension study were treated open-label with either 600 mg or 2,000 mg ocrelizumab.

At week 96, the mean ARR was 0.18 for patients who received open-label ocrelizumab 600 mg and 0.22 for those who received 2,000 mg. Overall, 67.3% of patients who took the 600-mg dose and 76.4% of patients who took the 2,000-mg dose were free of any clinical disease activity (no relapses or progression on the Expanded Disability Status Scale). In addition, 78.2% and 80.0% of patients, respectively, remained relapse-free. There were no GdE T1 lesions observed.

Exploratory analyses showed that patients who had switched to using ocrelizumab after placebo or IFNB-1a experienced benefits similar to those in patients who had remained on ocrelizumab therapy.

ATAMS was supported by Merck Serono and EMD Serono. The ocrelizumab trial was supported by F. Hoffman-La Roche. and Biogen Idec. Dr. Kappos and many of his coauthors have received institutional research support from those companies and other pharmaceutical developers of MS therapies. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis. Dr. Coetzee had no disclosures.

AMSTERDAM – While the B-cell targeted drug atacicept failed to improve disease activity in patients with relapsing remitting multiple sclerosis and even may have made the patients’ conditions worse, another anti–B-cell drug, ocrelizumab, is showing positive signs of being a future treatment for the disease.

Even though atacicept decreased mature B-cell proliferation and levels of serum immunoglobulins in the ATAMS (Atacicept in Multiple Sclerosis) randomized, phase II study – as would have been expected – patients who received atacicept had a higher annualized relapse rate (ARR) and more gadolinium-enhancing (GdE) lesions than did those on placebo. Atacicept is a recombinant fusion protein containing the soluble TACI receptor. It binds to and neutralizes the B-cell stimulatory cytokines B-Lymphocyte Stimulator and A Proliferation-Inducing Ligand and also blocks the activation of TACI receptors on mature B cells.

Data from a separate multicenter, randomized trial with ocrelizumab appear in stark contrast to the ATAMS study, as ocrelizumab clearly had a beneficial effect on the number of GdE lesions and ARR, and the findings appear to persist in the long term. Ocrelizumab is a humanized monoclonal antibody that targets CD-20 on the surface of B cells, much like rituximab (Rituxan), which has also been investigated as a potential MS therapy.

At the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), where the ATAMS results were presented, Dr. Ralf Gold of St. Josef Hospital and St. Elisabeth Hospital, both in Bochum, Germany, commented that the ATAMS findings came as a surprise because multiple studies have indicated a clear rationale for targeting B cells in MS.

"B cells have regulatory capacities [and] it may be that [with atacicept] you may impair regulatory pathways rather than silence the active and putative pathogenic B cells," Dr. Gold suggested. "Our immune system is very selective," he said, adding that there may be other explanations that would no doubt be discussed when the ATAMS data are published.

"B cells play a multifaceted role in the immune system and ... there can be unintended consequences for a therapy based on our incomplete understanding of B-cell biology," said Timothy Coetzee, Ph.D., the chief research officer of the National MS Society in the United States.

Dr. Coetzee, who was not involved in either study, noted in an interview that the ATAMS findings in particular highlight the complexity of B-cell signaling in MS.

"Although there is much we know about B cells, our understanding of these cells continues to evolve as we discover that they have new and unexpected roles to play." he said. "I suspect that that is what we saw with ATAMS. This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

"B cells play a multifaceted role in the immune system."

In ATAMS, the ARR for atacicept after 36 weeks was 0.86 with the 25-mg dose, 0.79 with the 75-mg dose, and 0.96 with the 150-mg dose, compared with 0.38 for placebo. In addition, patients who were given the experimental drug showed evidence of more, not fewer, GdE T1 lesions on MRI, which was the study’s primary end point.

The ATAMS study was halted early, in September 2009, after an independent data safety monitoring board identified these negative findings, Dr. Ludwig Kappos, chair of neurology at the University Hospital Basel (Switzerland), said at the congress.

Speaking on behalf of the ATAMS study group, Dr. Kappos noted that the apparently detrimental effects of atacicept appear to be reversed in the long term once treatment has stopped. The ATAMS trial protocol was amended to allow all patients who had been randomized into the trial to participate in an extended follow-up study for safety.

Of 255 patients who were enrolled in the trial, 184 underwent an extended 60-week evaluation. During this time, the mean ARR seen with two of the three doses of atacicept fell to rates similar to placebo, at 0.25 for the 25-mg dose (P less than .001 vs. placebo) and 0.29 for the 75-mg dose (P equals .014 vs. placebo), and 0.27 for placebo. The ARR for the 150-mg dose was 0.45.

"At least it was reassuring to observe that the negative effect that we might have had with this agent was reversed and did not persist over the end of treatment period," Dr. Kappos said.

He noted that at baseline there were higher percentages of patients in the atacicept groups who had no signs of GdE T1 lesions than there were in patients who received placebo (61.5% to 68.3% vs. 54%). There also was prior to treatment a higher mean number of GdE T1 lesions in placebo-treated patients, compared with patients who received atacicept at a dose of 25 mg or 75 mg (4.1 vs. 2.1 and 3.7, respectively). There were 4.7 GdE T1 lesions at baseline in patients treated with 150 mg.

Whether this slight imbalance in baseline characteristics or the manner in which atacicept targets B cells had any effect on the study’s outcomes remains to be seen, Dr. Kappos said.

In the other phase II trial, 220 patients with relapsing remitting MS who were randomized to receive two cycles of ocrelizumab for a total infusion dose of 600 mg or 2,000 mg, given in two divided doses of 300 mg or 1,000 mg, respectively, separated by 14 days. Other patients were given matching placebo infusions or open-label (rater-blinded) intramuscular interferon beta-1a (IFNB-1a, Avonex) 30 mcg once weekly.

Ocrelizumab not only significantly reduced the ARR by 73%-80%, but also reduced the mean number of GdE T1 lesions by 86%-96% versus placebo (P less than .0001). The ARRs for ocrelizumab at 24 weeks were significantly reduced with 600 mg and 2,000 mg ocrelizumab, compared with placebo, and, in an exploratory analysis, with IFNB-1a. The ARRs were 0.13 for the 600-mg dose and 0.17 for the 2,000-mg dose, compared with 0.64 for placebo and 0.36 for IFNB-1a, reported Dr. Kappos, who also was lead author on this study (Lancet 2011 Nov. 1 [doi:10.1016/S0140-6736(11)61649-8]).

"This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

The mean total number of GdE T1 lesions over weeks 12, 16, 20, and 24 was 0.8 for both 600 mg and 2,000 mg ocrelizumab, which was significantly different from the mean of 6.6 lesions observed in the placebo group.

The study shows "the effectiveness of B cell depletion with both ocrelizumab doses ... with favorable short-term safety profile," according to the study authors. Dr. Kappos also recently presented long-term data from the trial in a poster at the congress.

After week 24, all 183 patients who continued to participate in the 96-week extension study were treated open-label with either 600 mg or 2,000 mg ocrelizumab.

At week 96, the mean ARR was 0.18 for patients who received open-label ocrelizumab 600 mg and 0.22 for those who received 2,000 mg. Overall, 67.3% of patients who took the 600-mg dose and 76.4% of patients who took the 2,000-mg dose were free of any clinical disease activity (no relapses or progression on the Expanded Disability Status Scale). In addition, 78.2% and 80.0% of patients, respectively, remained relapse-free. There were no GdE T1 lesions observed.

Exploratory analyses showed that patients who had switched to using ocrelizumab after placebo or IFNB-1a experienced benefits similar to those in patients who had remained on ocrelizumab therapy.

ATAMS was supported by Merck Serono and EMD Serono. The ocrelizumab trial was supported by F. Hoffman-La Roche. and Biogen Idec. Dr. Kappos and many of his coauthors have received institutional research support from those companies and other pharmaceutical developers of MS therapies. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis. Dr. Coetzee had no disclosures.

AMSTERDAM – While the B-cell targeted drug atacicept failed to improve disease activity in patients with relapsing remitting multiple sclerosis and even may have made the patients’ conditions worse, another anti–B-cell drug, ocrelizumab, is showing positive signs of being a future treatment for the disease.

Even though atacicept decreased mature B-cell proliferation and levels of serum immunoglobulins in the ATAMS (Atacicept in Multiple Sclerosis) randomized, phase II study – as would have been expected – patients who received atacicept had a higher annualized relapse rate (ARR) and more gadolinium-enhancing (GdE) lesions than did those on placebo. Atacicept is a recombinant fusion protein containing the soluble TACI receptor. It binds to and neutralizes the B-cell stimulatory cytokines B-Lymphocyte Stimulator and A Proliferation-Inducing Ligand and also blocks the activation of TACI receptors on mature B cells.

Data from a separate multicenter, randomized trial with ocrelizumab appear in stark contrast to the ATAMS study, as ocrelizumab clearly had a beneficial effect on the number of GdE lesions and ARR, and the findings appear to persist in the long term. Ocrelizumab is a humanized monoclonal antibody that targets CD-20 on the surface of B cells, much like rituximab (Rituxan), which has also been investigated as a potential MS therapy.

At the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), where the ATAMS results were presented, Dr. Ralf Gold of St. Josef Hospital and St. Elisabeth Hospital, both in Bochum, Germany, commented that the ATAMS findings came as a surprise because multiple studies have indicated a clear rationale for targeting B cells in MS.

"B cells have regulatory capacities [and] it may be that [with atacicept] you may impair regulatory pathways rather than silence the active and putative pathogenic B cells," Dr. Gold suggested. "Our immune system is very selective," he said, adding that there may be other explanations that would no doubt be discussed when the ATAMS data are published.

"B cells play a multifaceted role in the immune system and ... there can be unintended consequences for a therapy based on our incomplete understanding of B-cell biology," said Timothy Coetzee, Ph.D., the chief research officer of the National MS Society in the United States.

Dr. Coetzee, who was not involved in either study, noted in an interview that the ATAMS findings in particular highlight the complexity of B-cell signaling in MS.

"Although there is much we know about B cells, our understanding of these cells continues to evolve as we discover that they have new and unexpected roles to play." he said. "I suspect that that is what we saw with ATAMS. This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

"B cells play a multifaceted role in the immune system."

In ATAMS, the ARR for atacicept after 36 weeks was 0.86 with the 25-mg dose, 0.79 with the 75-mg dose, and 0.96 with the 150-mg dose, compared with 0.38 for placebo. In addition, patients who were given the experimental drug showed evidence of more, not fewer, GdE T1 lesions on MRI, which was the study’s primary end point.

The ATAMS study was halted early, in September 2009, after an independent data safety monitoring board identified these negative findings, Dr. Ludwig Kappos, chair of neurology at the University Hospital Basel (Switzerland), said at the congress.

Speaking on behalf of the ATAMS study group, Dr. Kappos noted that the apparently detrimental effects of atacicept appear to be reversed in the long term once treatment has stopped. The ATAMS trial protocol was amended to allow all patients who had been randomized into the trial to participate in an extended follow-up study for safety.

Of 255 patients who were enrolled in the trial, 184 underwent an extended 60-week evaluation. During this time, the mean ARR seen with two of the three doses of atacicept fell to rates similar to placebo, at 0.25 for the 25-mg dose (P less than .001 vs. placebo) and 0.29 for the 75-mg dose (P equals .014 vs. placebo), and 0.27 for placebo. The ARR for the 150-mg dose was 0.45.

"At least it was reassuring to observe that the negative effect that we might have had with this agent was reversed and did not persist over the end of treatment period," Dr. Kappos said.

He noted that at baseline there were higher percentages of patients in the atacicept groups who had no signs of GdE T1 lesions than there were in patients who received placebo (61.5% to 68.3% vs. 54%). There also was prior to treatment a higher mean number of GdE T1 lesions in placebo-treated patients, compared with patients who received atacicept at a dose of 25 mg or 75 mg (4.1 vs. 2.1 and 3.7, respectively). There were 4.7 GdE T1 lesions at baseline in patients treated with 150 mg.

Whether this slight imbalance in baseline characteristics or the manner in which atacicept targets B cells had any effect on the study’s outcomes remains to be seen, Dr. Kappos said.

In the other phase II trial, 220 patients with relapsing remitting MS who were randomized to receive two cycles of ocrelizumab for a total infusion dose of 600 mg or 2,000 mg, given in two divided doses of 300 mg or 1,000 mg, respectively, separated by 14 days. Other patients were given matching placebo infusions or open-label (rater-blinded) intramuscular interferon beta-1a (IFNB-1a, Avonex) 30 mcg once weekly.

Ocrelizumab not only significantly reduced the ARR by 73%-80%, but also reduced the mean number of GdE T1 lesions by 86%-96% versus placebo (P less than .0001). The ARRs for ocrelizumab at 24 weeks were significantly reduced with 600 mg and 2,000 mg ocrelizumab, compared with placebo, and, in an exploratory analysis, with IFNB-1a. The ARRs were 0.13 for the 600-mg dose and 0.17 for the 2,000-mg dose, compared with 0.64 for placebo and 0.36 for IFNB-1a, reported Dr. Kappos, who also was lead author on this study (Lancet 2011 Nov. 1 [doi:10.1016/S0140-6736(11)61649-8]).

"This doesn’t mean that we won’t have B-cell specific treatments for MS; however, we have more work to do in this area."

The mean total number of GdE T1 lesions over weeks 12, 16, 20, and 24 was 0.8 for both 600 mg and 2,000 mg ocrelizumab, which was significantly different from the mean of 6.6 lesions observed in the placebo group.

The study shows "the effectiveness of B cell depletion with both ocrelizumab doses ... with favorable short-term safety profile," according to the study authors. Dr. Kappos also recently presented long-term data from the trial in a poster at the congress.

After week 24, all 183 patients who continued to participate in the 96-week extension study were treated open-label with either 600 mg or 2,000 mg ocrelizumab.

At week 96, the mean ARR was 0.18 for patients who received open-label ocrelizumab 600 mg and 0.22 for those who received 2,000 mg. Overall, 67.3% of patients who took the 600-mg dose and 76.4% of patients who took the 2,000-mg dose were free of any clinical disease activity (no relapses or progression on the Expanded Disability Status Scale). In addition, 78.2% and 80.0% of patients, respectively, remained relapse-free. There were no GdE T1 lesions observed.

Exploratory analyses showed that patients who had switched to using ocrelizumab after placebo or IFNB-1a experienced benefits similar to those in patients who had remained on ocrelizumab therapy.

ATAMS was supported by Merck Serono and EMD Serono. The ocrelizumab trial was supported by F. Hoffman-La Roche. and Biogen Idec. Dr. Kappos and many of his coauthors have received institutional research support from those companies and other pharmaceutical developers of MS therapies. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis. Dr. Coetzee had no disclosures.

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.

AMSTERDAM – Significant percentages of patients with relapsing-remitting multiple sclerosis who discontinue natalizumab but start another medication experience a return of disease activity within 12 weeks, according to the results of the RESTORE study.

The risk of return of disease activity during treatment interruption was "notable" even with the use of interferon beta-1a (IFNB-1a, Avonex); glatiramer acetate (Copaxone); or methylprednisolone in place of natalizumab in the study of 175 patients, Dr. Robert Fox said during a late-breaking trials session at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The risk of temporarily stopping natalizumab generally appeared to outweigh its benefits in this exploratory study, said Dr. Fox, the lead investigator of the study and medical director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Interrupting treatment with natalizumab has been proposed as a possible way to reduce the risk of progressive multifocal leukoencephalopathy, a rare and potentially fatal opportunistic disease caused by the JC virus. It has been associated with prolonged natalizumab therapy.

In RESTORE, all patients had been treated for 1 year or longer and were relapse free before treatment with natalizumab (given at 300 mg IV once every 4 weeks) was interrupted for 24 weeks. The investigators randomized patients to continue natalizumab treatment (n = 45), stop natalizumab and receive IV placebo (n = 42), or stop natalizumab and receive 1,000 mg IV methylprednisolone every 4 weeks (n = 54), 30 mg intramuscular IFNB-1a once per week (n = 17), or 20 mg subcutaneous glatiramer acetate once daily (n = 17) for 24 weeks, followed by re-instatement of natalizumab infusions for an additional 24 weeks. Investigators at each of the study’s 31 clinical sites selected the choice of alternative treatment.

Increased disease activity on MRI was defined as the occurrence of at least one new gadolinium-enhancing (GdE) lesion greater than 0.8 cm³ in volume or two or more GdE lesions of any size.

Dr. Fox reported that 75% of patients met rescue criteria within weeks 16 to 20, but the first signs of increased disease activity on MRI were noted as early as 12 weeks. In these patients, rescue treatment, consisting of high-dose corticosteroids or restarting natalizumab, was required by 44% on placebo, 53% on glatiramer acetate, 40% on methylprednisolone, and 7% on IFNB-1a.

Clinical relapse, assessed using the Expanded Disability Status Scale (EDSS), occurred in 17% of placebo-treated patients, 4% of patients who continued natalizumab, and 29% treated with IFNB-1a, 27% with glatiramer acetate, and 15% with methylprednisolone. Most relapses occurred around weeks 14-16, but could occur as early as 4-8 weeks.

Overall, the estimated percentage of patients who had a clinical relapse or MRI scan that met rescue criteria was 61% for placebo, 60% for glatiramer acetate, 55% for methylprednisolone, 29% for IFNB-1a, and 5% for natalizumab continuation.

"Interferon appeared a bit better at suppressing MRI disease activity than the other open-label therapies, although this group did have a lower disease activity prior to natalizumab therapy," Dr. Fox said.

He added that the study was not designed or powered to detect differences in the effects of the three alternative immunomodulating therapies used and that "monthly methylprednisolone, at least at the dose we used here in this trial, does not appear to be effective in suppressing disease activity."

Dr. Fox suggested that clinicians who may be considering trying to stop natalizumab in their patients may be advised to undertake monthly MRI, starting 3 months after the last natalizumab dose is given, but the practicality of this approach needs to be taken into consideration. He also suggested considering rescue therapy if GdE lesions appear or a patient has a clinical relapse.

"Perhaps we should be doing a weaning process. There may be ways to do this without doing it abruptly," suggested Dr. Daniel Kantor, who was not involved in the study.

"When I stop [natalizumab], I give people pulsed ACTH [adrenocorticotropic hormone] ... the point being that even when you are on a ‘drug holiday’ you can’t just be on nothing," Dr. Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said in an interview.

Biogen Idec and Elan Pharmaceuticals sponsored the trial. Dr. Fox said he has received consultant fees from Avanir, Biogen Idec, EMD Serono, and Novartis and research support from Biogen Idec. Dr. Kantor said he has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, and Novartis.

AMSTERDAM – Daclizumab reduced the rate of relapse and the rate of disability progression in patients with relapsing-remitting multiple sclerosis in a 1-year, placebo-controlled phase II trial .

The novel immunomodulatory therapy also reduced the number of new brain lesions detected on MRI while producing a very low rate of treatment discontinuation and a low rate of injection site reactions, [which is] consistent with a very good tolerability profile," study investigator Dr. Gavin Giovannoni said at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Daclizumab (Zenapax) is a humanized monoclonal antibody targeted against the CD25 alpha subunit of the interleukin-2 receptor. It is currently approved for the prophylaxis of acute organ rejection in patients receiving renal transplants. Although it is not clear how daclizumab works, it is thought that the drug reduces the number of activated T cells and increases natural killer cell proliferation (J. Immunol. 2010;185:1311-20).

In the multicenter, double-blind SELECT study, 600 patients were randomized to receive subcutaneous injections of one of two doses of daclizumab (150 mg or 300 mg) or placebo every 4 weeks for up to 1 year.

Patients were eligible for the study if they had a diagnosis of relapsing-remitting multiple sclerosis confirmed with McDonald 2005 criteria and at least one relapse in the past 12 months with brain MRI consistent with MS or gadolinium-enhanced (GdE) lesion activity in the 6 weeks prior to randomization.

In an MRI substudy, 309 patients underwent monthly brain scans while the remaining study population underwent MRI at four time points: before treatment, 24 weeks after randomization, 26 weeks after randomization, and then 52 weeks after randomization. At baseline, the two groups of patients had a median age of 35-37 years and a median time since diagnosis of 2-3 years. About three-quarters of patients were treatment naive and had experienced 1.3-1.4 relapses in the past year. However, 52% of patients randomized to 150 mg daclizumab had one or more GdE lesions – a higher rate than that seen in either the 300-mg daclizumab or placebo groups (36% and 44%), reported Dr. Giovannoni of Queen Mary University in London.

At 1 year, the annualized relapse rate was 0.46 for placebo, 0.21 for daclizumab 150 mg, and 0.23 for daclizumab 300 mg. This represented reductions of 54% and 50%, respectively, in the rates of relapse, which were significant in comparison with placebo.

The percentage of patients who remained relapse free was 81% for daclizumab 150 mg and 80 % for daclizumab 300 mg; both rates were significantly better than for placebo (64%).

The percentage of patients with 3-month confirmed disability progression was 5.9% for the 150-mg dose, 7.8% for the 300-mg dose, and 13.3% for placebo. This was a "surprising result considering this was only a 52-week study [of] the impact of daclizumab on disability progression," Dr. Giovannoni said.

He and his coinvestigators also observed quality of life improvements with daclizumab treatment on physical scores on the Multiple Sclerosis Impact Scale–29, compared with placebo.

Results of the MRI substudy showed a significant 69%-78% reduction in new or enlarging GdE lesions between weeks 8 and 24 of the study in patients treated with daclizumab versus placebo, and a 79%-86% reduction in new or enlarging GdE lesions by the end of the 1-year study.

Adverse events occurred more often among patients in the daclizumab groups (72%-76% vs. 28% with placebo), but any serious event was more likely to occur in patients randomized to placebo (27% vs. 16%-18% for daclizumab).

One death potentially related to treatment occurred in the daclizumab arm. This was due to a complication of a psoas abscess occurring in a patient recovering from a serious cutaneous adverse event.

"The results of this trial have informed the ongoing [clinical trials] program, and monitoring and treatment algorithms have been put in place to mitigate any safety concerns," Dr. Giovannoni said.

Another two clinical studies of daclizumab are currently ongoing – an open-label, multicenter extension of the SELECT study and the phase III DECIDE trial. This latter trial is comparing up to 144 weeks of treatment with daclizumab against interferon beta-1a (Avonex) in about 1,500 patients with relapsing-remitting multiple sclerosis. Primary data from the trial are unlikely to be available until late 2013.

The SELECT study was supported by Biogen Idec and Abbot Biotherapeutics. Dr. Giovannoni disclosed receiving research support and/or consulting fees from Bayer Healthcare, Biogen Idec, and other manufacturers of MS therapies.

AMSTERDAM – Daclizumab reduced the rate of relapse and the rate of disability progression in patients with relapsing-remitting multiple sclerosis in a 1-year, placebo-controlled phase II trial .

The novel immunomodulatory therapy also reduced the number of new brain lesions detected on MRI while producing a very low rate of treatment discontinuation and a low rate of injection site reactions, [which is] consistent with a very good tolerability profile," study investigator Dr. Gavin Giovannoni said at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Daclizumab (Zenapax) is a humanized monoclonal antibody targeted against the CD25 alpha subunit of the interleukin-2 receptor. It is currently approved for the prophylaxis of acute organ rejection in patients receiving renal transplants. Although it is not clear how daclizumab works, it is thought that the drug reduces the number of activated T cells and increases natural killer cell proliferation (J. Immunol. 2010;185:1311-20).

In the multicenter, double-blind SELECT study, 600 patients were randomized to receive subcutaneous injections of one of two doses of daclizumab (150 mg or 300 mg) or placebo every 4 weeks for up to 1 year.

Patients were eligible for the study if they had a diagnosis of relapsing-remitting multiple sclerosis confirmed with McDonald 2005 criteria and at least one relapse in the past 12 months with brain MRI consistent with MS or gadolinium-enhanced (GdE) lesion activity in the 6 weeks prior to randomization.

In an MRI substudy, 309 patients underwent monthly brain scans while the remaining study population underwent MRI at four time points: before treatment, 24 weeks after randomization, 26 weeks after randomization, and then 52 weeks after randomization. At baseline, the two groups of patients had a median age of 35-37 years and a median time since diagnosis of 2-3 years. About three-quarters of patients were treatment naive and had experienced 1.3-1.4 relapses in the past year. However, 52% of patients randomized to 150 mg daclizumab had one or more GdE lesions – a higher rate than that seen in either the 300-mg daclizumab or placebo groups (36% and 44%), reported Dr. Giovannoni of Queen Mary University in London.

At 1 year, the annualized relapse rate was 0.46 for placebo, 0.21 for daclizumab 150 mg, and 0.23 for daclizumab 300 mg. This represented reductions of 54% and 50%, respectively, in the rates of relapse, which were significant in comparison with placebo.

The percentage of patients who remained relapse free was 81% for daclizumab 150 mg and 80 % for daclizumab 300 mg; both rates were significantly better than for placebo (64%).

The percentage of patients with 3-month confirmed disability progression was 5.9% for the 150-mg dose, 7.8% for the 300-mg dose, and 13.3% for placebo. This was a "surprising result considering this was only a 52-week study [of] the impact of daclizumab on disability progression," Dr. Giovannoni said.

He and his coinvestigators also observed quality of life improvements with daclizumab treatment on physical scores on the Multiple Sclerosis Impact Scale–29, compared with placebo.

Results of the MRI substudy showed a significant 69%-78% reduction in new or enlarging GdE lesions between weeks 8 and 24 of the study in patients treated with daclizumab versus placebo, and a 79%-86% reduction in new or enlarging GdE lesions by the end of the 1-year study.

Adverse events occurred more often among patients in the daclizumab groups (72%-76% vs. 28% with placebo), but any serious event was more likely to occur in patients randomized to placebo (27% vs. 16%-18% for daclizumab).

One death potentially related to treatment occurred in the daclizumab arm. This was due to a complication of a psoas abscess occurring in a patient recovering from a serious cutaneous adverse event.

"The results of this trial have informed the ongoing [clinical trials] program, and monitoring and treatment algorithms have been put in place to mitigate any safety concerns," Dr. Giovannoni said.

Another two clinical studies of daclizumab are currently ongoing – an open-label, multicenter extension of the SELECT study and the phase III DECIDE trial. This latter trial is comparing up to 144 weeks of treatment with daclizumab against interferon beta-1a (Avonex) in about 1,500 patients with relapsing-remitting multiple sclerosis. Primary data from the trial are unlikely to be available until late 2013.

The SELECT study was supported by Biogen Idec and Abbot Biotherapeutics. Dr. Giovannoni disclosed receiving research support and/or consulting fees from Bayer Healthcare, Biogen Idec, and other manufacturers of MS therapies.

AMSTERDAM – Daclizumab reduced the rate of relapse and the rate of disability progression in patients with relapsing-remitting multiple sclerosis in a 1-year, placebo-controlled phase II trial .

The novel immunomodulatory therapy also reduced the number of new brain lesions detected on MRI while producing a very low rate of treatment discontinuation and a low rate of injection site reactions, [which is] consistent with a very good tolerability profile," study investigator Dr. Gavin Giovannoni said at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Daclizumab (Zenapax) is a humanized monoclonal antibody targeted against the CD25 alpha subunit of the interleukin-2 receptor. It is currently approved for the prophylaxis of acute organ rejection in patients receiving renal transplants. Although it is not clear how daclizumab works, it is thought that the drug reduces the number of activated T cells and increases natural killer cell proliferation (J. Immunol. 2010;185:1311-20).

In the multicenter, double-blind SELECT study, 600 patients were randomized to receive subcutaneous injections of one of two doses of daclizumab (150 mg or 300 mg) or placebo every 4 weeks for up to 1 year.

Patients were eligible for the study if they had a diagnosis of relapsing-remitting multiple sclerosis confirmed with McDonald 2005 criteria and at least one relapse in the past 12 months with brain MRI consistent with MS or gadolinium-enhanced (GdE) lesion activity in the 6 weeks prior to randomization.

In an MRI substudy, 309 patients underwent monthly brain scans while the remaining study population underwent MRI at four time points: before treatment, 24 weeks after randomization, 26 weeks after randomization, and then 52 weeks after randomization. At baseline, the two groups of patients had a median age of 35-37 years and a median time since diagnosis of 2-3 years. About three-quarters of patients were treatment naive and had experienced 1.3-1.4 relapses in the past year. However, 52% of patients randomized to 150 mg daclizumab had one or more GdE lesions – a higher rate than that seen in either the 300-mg daclizumab or placebo groups (36% and 44%), reported Dr. Giovannoni of Queen Mary University in London.

At 1 year, the annualized relapse rate was 0.46 for placebo, 0.21 for daclizumab 150 mg, and 0.23 for daclizumab 300 mg. This represented reductions of 54% and 50%, respectively, in the rates of relapse, which were significant in comparison with placebo.

The percentage of patients who remained relapse free was 81% for daclizumab 150 mg and 80 % for daclizumab 300 mg; both rates were significantly better than for placebo (64%).

The percentage of patients with 3-month confirmed disability progression was 5.9% for the 150-mg dose, 7.8% for the 300-mg dose, and 13.3% for placebo. This was a "surprising result considering this was only a 52-week study [of] the impact of daclizumab on disability progression," Dr. Giovannoni said.

He and his coinvestigators also observed quality of life improvements with daclizumab treatment on physical scores on the Multiple Sclerosis Impact Scale–29, compared with placebo.

Results of the MRI substudy showed a significant 69%-78% reduction in new or enlarging GdE lesions between weeks 8 and 24 of the study in patients treated with daclizumab versus placebo, and a 79%-86% reduction in new or enlarging GdE lesions by the end of the 1-year study.

Adverse events occurred more often among patients in the daclizumab groups (72%-76% vs. 28% with placebo), but any serious event was more likely to occur in patients randomized to placebo (27% vs. 16%-18% for daclizumab).

One death potentially related to treatment occurred in the daclizumab arm. This was due to a complication of a psoas abscess occurring in a patient recovering from a serious cutaneous adverse event.

"The results of this trial have informed the ongoing [clinical trials] program, and monitoring and treatment algorithms have been put in place to mitigate any safety concerns," Dr. Giovannoni said.

Another two clinical studies of daclizumab are currently ongoing – an open-label, multicenter extension of the SELECT study and the phase III DECIDE trial. This latter trial is comparing up to 144 weeks of treatment with daclizumab against interferon beta-1a (Avonex) in about 1,500 patients with relapsing-remitting multiple sclerosis. Primary data from the trial are unlikely to be available until late 2013.

The SELECT study was supported by Biogen Idec and Abbot Biotherapeutics. Dr. Giovannoni disclosed receiving research support and/or consulting fees from Bayer Healthcare, Biogen Idec, and other manufacturers of MS therapies.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.