ECTRIMS: European Committee for Treatment and Research in Multiple Sclerosis

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Dimethyl fumarate and teriflunomide have similar efficacy in terms of risk of relapse and worsening of Expanded Disability Status Scale (EDSS) score after one and two years of treatment, according to data presented at ECTRIMS 2018. Significantly more patients have new T2 lesions after two years of teriflunomide, however, compared with dimethyl fumarate, and this outcome may explain an increased treatment withdrawal for lack of efficacy among patients receiving teriflunomide.

Teriflunomide and dimethyl fumarate have been approved as first-line treatments for patients with relapsing-remitting multiple sclerosis (MS). To date, no randomized controlled nor observational studies have compared their relative efficacies. David A. Laplaud, MD, PhD, a team leader at the Center of Research in Transplantation and Immunology in Nantes, France, and colleagues conducted a study to compare the effects of teriflunomide and dimethyl fumarate on clinical and MRI outcomes in patients with relapsing-remitting MS from 34 MS centers participating in the French prospective national cohort of MS patients.

The investigators included 1,770 patients with relapsing-remitting MS in the study. In all, 713 participants received teriflunomide, and 1,057 received dimethyl fumarate. Participants were aged 18 to 65 and had an EDSS score of 0 to 5.5 and an available brain MRI performed within six months before treatment initiation. The outcomes under investigation were the proportion of patients with at least one relapse in the year and the two years following teriflunomide or dimethyl fumarate initiation, the proportion of patients with at least one new T2 lesion at one and two years, the number of patients with an increased EDSS score at one and two years, and reasons for treatment cessation at one and two years. For statistical analyses, the outcomes were modeled with propensity scores and logistic regressions by using weighted likelihood maximization and a robust variance estimator.

The confounder-adjusted proportion of patients with at least one relapse at one and two years of treatment was similar in the teriflunomide group and the dimethyl fumarate group (21.6% vs 20.2% for the first year, 30.4% vs 29.5% at two years). Likewise, a similar percentage of patients had an increase of EDSS score at one and two years in the teriflunomide group (27.4% and 41.6%, respectively) and the dimethyl fumarate group (27.1% and 40.6%, respectively). MRI comparisons, however, revealed that the confounder-adjusted proportion of patients with at least one new T2 lesion at two years was significantly lower in patients treated with dimethyl fumarate, compared with teriflunomide (60.8% vs 72.2%; odds ratio [OR], 0.6). The reason for treatment withdrawal at two years was lack of efficacy in 8.5% of patients who received dimethyl fumarate versus 14.5% of patients who received teriflunomide (OR, 0.54).

BERLIN—Dimethyl fumarate and teriflunomide have similar efficacy in terms of risk of relapse and worsening of Expanded Disability Status Scale (EDSS) score after one and two years of treatment, according to data presented at ECTRIMS 2018. Significantly more patients have new T2 lesions after two years of teriflunomide, however, compared with dimethyl fumarate, and this outcome may explain an increased treatment withdrawal for lack of efficacy among patients receiving teriflunomide.

Teriflunomide and dimethyl fumarate have been approved as first-line treatments for patients with relapsing-remitting multiple sclerosis (MS). To date, no randomized controlled nor observational studies have compared their relative efficacies. David A. Laplaud, MD, PhD, a team leader at the Center of Research in Transplantation and Immunology in Nantes, France, and colleagues conducted a study to compare the effects of teriflunomide and dimethyl fumarate on clinical and MRI outcomes in patients with relapsing-remitting MS from 34 MS centers participating in the French prospective national cohort of MS patients.

The investigators included 1,770 patients with relapsing-remitting MS in the study. In all, 713 participants received teriflunomide, and 1,057 received dimethyl fumarate. Participants were aged 18 to 65 and had an EDSS score of 0 to 5.5 and an available brain MRI performed within six months before treatment initiation. The outcomes under investigation were the proportion of patients with at least one relapse in the year and the two years following teriflunomide or dimethyl fumarate initiation, the proportion of patients with at least one new T2 lesion at one and two years, the number of patients with an increased EDSS score at one and two years, and reasons for treatment cessation at one and two years. For statistical analyses, the outcomes were modeled with propensity scores and logistic regressions by using weighted likelihood maximization and a robust variance estimator.

The confounder-adjusted proportion of patients with at least one relapse at one and two years of treatment was similar in the teriflunomide group and the dimethyl fumarate group (21.6% vs 20.2% for the first year, 30.4% vs 29.5% at two years). Likewise, a similar percentage of patients had an increase of EDSS score at one and two years in the teriflunomide group (27.4% and 41.6%, respectively) and the dimethyl fumarate group (27.1% and 40.6%, respectively). MRI comparisons, however, revealed that the confounder-adjusted proportion of patients with at least one new T2 lesion at two years was significantly lower in patients treated with dimethyl fumarate, compared with teriflunomide (60.8% vs 72.2%; odds ratio [OR], 0.6). The reason for treatment withdrawal at two years was lack of efficacy in 8.5% of patients who received dimethyl fumarate versus 14.5% of patients who received teriflunomide (OR, 0.54).

BERLIN—Dimethyl fumarate and teriflunomide have similar efficacy in terms of risk of relapse and worsening of Expanded Disability Status Scale (EDSS) score after one and two years of treatment, according to data presented at ECTRIMS 2018. Significantly more patients have new T2 lesions after two years of teriflunomide, however, compared with dimethyl fumarate, and this outcome may explain an increased treatment withdrawal for lack of efficacy among patients receiving teriflunomide.

Teriflunomide and dimethyl fumarate have been approved as first-line treatments for patients with relapsing-remitting multiple sclerosis (MS). To date, no randomized controlled nor observational studies have compared their relative efficacies. David A. Laplaud, MD, PhD, a team leader at the Center of Research in Transplantation and Immunology in Nantes, France, and colleagues conducted a study to compare the effects of teriflunomide and dimethyl fumarate on clinical and MRI outcomes in patients with relapsing-remitting MS from 34 MS centers participating in the French prospective national cohort of MS patients.

The investigators included 1,770 patients with relapsing-remitting MS in the study. In all, 713 participants received teriflunomide, and 1,057 received dimethyl fumarate. Participants were aged 18 to 65 and had an EDSS score of 0 to 5.5 and an available brain MRI performed within six months before treatment initiation. The outcomes under investigation were the proportion of patients with at least one relapse in the year and the two years following teriflunomide or dimethyl fumarate initiation, the proportion of patients with at least one new T2 lesion at one and two years, the number of patients with an increased EDSS score at one and two years, and reasons for treatment cessation at one and two years. For statistical analyses, the outcomes were modeled with propensity scores and logistic regressions by using weighted likelihood maximization and a robust variance estimator.

The confounder-adjusted proportion of patients with at least one relapse at one and two years of treatment was similar in the teriflunomide group and the dimethyl fumarate group (21.6% vs 20.2% for the first year, 30.4% vs 29.5% at two years). Likewise, a similar percentage of patients had an increase of EDSS score at one and two years in the teriflunomide group (27.4% and 41.6%, respectively) and the dimethyl fumarate group (27.1% and 40.6%, respectively). MRI comparisons, however, revealed that the confounder-adjusted proportion of patients with at least one new T2 lesion at two years was significantly lower in patients treated with dimethyl fumarate, compared with teriflunomide (60.8% vs 72.2%; odds ratio [OR], 0.6). The reason for treatment withdrawal at two years was lack of efficacy in 8.5% of patients who received dimethyl fumarate versus 14.5% of patients who received teriflunomide (OR, 0.54).

BERLIN—Widespread focal cortical damage at multiple sclerosis (MS) onset identifies patients likely to have frequent early relapses and a rapid development of progressive disease, which results from worsening global cortical pathology over time, according to a study presented at ECTRIMS 2018. The results provide a basis for patient stratification with the goal of therapeutic optimization. In addition, the data “highlight the importance of elucidating mechanisms involved in early cortical pathology,” according to the investigators.

Following Patients With Relapsing-Remitting MS

Among patients with relapsing-remitting MS, a high frequency of early relapses is associated with increased risk of developing severe disability, which suggests that early biologic mechanisms influence long-term disease evolution. Antonio Scalfari, MD, PhD, a consultant neurologist at Imperial College Healthcare in London, and colleagues sought to investigate the relationship between early cortical pathology, early relapses, and the risk of converting to secondary progressive MS.

Dr. Scalfari and colleagues examined 219 patients with relapsing-remitting MS. Participants had one (n = 116), two (n = 53), or three or more (n = 50) relapses during the first two years. Follow-up lasted for a mean of 7.9 years. The researchers assessed the number of cortical lesions and white matter lesions and the rate of cortical thinning using 3D double inversion recovery, 3D T1-weighted imaging, and Freesurfer analysis.

Cortical Lesions Predicted Cortical Thinning

During the observation period, 59 (27%) patients converted to secondary progressive MS in a mean of 6.1 years. At disease onset, the investigators detected 674 cortical lesions in 166 (76%) patients. A larger number of cortical lesions was associated with a significantly higher risk of secondary progressive MS. The hazard ratios (HR) for secondary progressive MS were 2.16 for patients with two lesions, 4.79 for patients with five lesions, and 12.3 for patients with seven lesions. A large number of cortical lesions also was associated with shorter latency to secondary progressive MS and a faster rate of global cortical thinning. The mean loss per year was 0.93% for patients with no lesions, 0.99% for patients with one to three lesions, 1.13% for patients with four to six lesions, and 1.33% for patients with seven or more lesions. In the group with no cortical lesions (n = 53), no patients entered the secondary progressive phase, and four reached an Expanded Disability Status Scale score of 4.

Patients with a high number of early relapses, compared with those with low and moderate numbers, had a larger volume of white matter lesions and cortical lesions at onset. The mean volumes of cortical lesions were 181.6 mm³, 386.8 mm³, and 544.0 mm³ for patients with one, two, and three or more early relapses, respectively. Patients with a high number of early relapses also accrued more cortical lesions (mean cortical lesion volumes were 118.8 mm³, 138.8 mm³, and 790.5 mm³ for patients with one, two, and three or more early relapses, respectively), had a faster rate of cortical atrophy (mean loss/year was 0.47%, 0.79%, and 0.94% for patients with one, two, and three or more early relapses, respectively), and entered the secondary progressive phase more rapidly.

In the multivariate model, older age at onset (HR, 1.97), a larger baseline cortical lesion (HR, 2.21) and white matter lesion (HR, 1.32) volume, early changes of global cortical thickness (HR, 1.36), and three or more early relapses (HR, 6.08) independently predicted a higher probability of secondary progressive MS.

BERLIN—Widespread focal cortical damage at multiple sclerosis (MS) onset identifies patients likely to have frequent early relapses and a rapid development of progressive disease, which results from worsening global cortical pathology over time, according to a study presented at ECTRIMS 2018. The results provide a basis for patient stratification with the goal of therapeutic optimization. In addition, the data “highlight the importance of elucidating mechanisms involved in early cortical pathology,” according to the investigators.

Following Patients With Relapsing-Remitting MS

Among patients with relapsing-remitting MS, a high frequency of early relapses is associated with increased risk of developing severe disability, which suggests that early biologic mechanisms influence long-term disease evolution. Antonio Scalfari, MD, PhD, a consultant neurologist at Imperial College Healthcare in London, and colleagues sought to investigate the relationship between early cortical pathology, early relapses, and the risk of converting to secondary progressive MS.

Dr. Scalfari and colleagues examined 219 patients with relapsing-remitting MS. Participants had one (n = 116), two (n = 53), or three or more (n = 50) relapses during the first two years. Follow-up lasted for a mean of 7.9 years. The researchers assessed the number of cortical lesions and white matter lesions and the rate of cortical thinning using 3D double inversion recovery, 3D T1-weighted imaging, and Freesurfer analysis.

Cortical Lesions Predicted Cortical Thinning

During the observation period, 59 (27%) patients converted to secondary progressive MS in a mean of 6.1 years. At disease onset, the investigators detected 674 cortical lesions in 166 (76%) patients. A larger number of cortical lesions was associated with a significantly higher risk of secondary progressive MS. The hazard ratios (HR) for secondary progressive MS were 2.16 for patients with two lesions, 4.79 for patients with five lesions, and 12.3 for patients with seven lesions. A large number of cortical lesions also was associated with shorter latency to secondary progressive MS and a faster rate of global cortical thinning. The mean loss per year was 0.93% for patients with no lesions, 0.99% for patients with one to three lesions, 1.13% for patients with four to six lesions, and 1.33% for patients with seven or more lesions. In the group with no cortical lesions (n = 53), no patients entered the secondary progressive phase, and four reached an Expanded Disability Status Scale score of 4.

Patients with a high number of early relapses, compared with those with low and moderate numbers, had a larger volume of white matter lesions and cortical lesions at onset. The mean volumes of cortical lesions were 181.6 mm³, 386.8 mm³, and 544.0 mm³ for patients with one, two, and three or more early relapses, respectively. Patients with a high number of early relapses also accrued more cortical lesions (mean cortical lesion volumes were 118.8 mm³, 138.8 mm³, and 790.5 mm³ for patients with one, two, and three or more early relapses, respectively), had a faster rate of cortical atrophy (mean loss/year was 0.47%, 0.79%, and 0.94% for patients with one, two, and three or more early relapses, respectively), and entered the secondary progressive phase more rapidly.

In the multivariate model, older age at onset (HR, 1.97), a larger baseline cortical lesion (HR, 2.21) and white matter lesion (HR, 1.32) volume, early changes of global cortical thickness (HR, 1.36), and three or more early relapses (HR, 6.08) independently predicted a higher probability of secondary progressive MS.

BERLIN—Widespread focal cortical damage at multiple sclerosis (MS) onset identifies patients likely to have frequent early relapses and a rapid development of progressive disease, which results from worsening global cortical pathology over time, according to a study presented at ECTRIMS 2018. The results provide a basis for patient stratification with the goal of therapeutic optimization. In addition, the data “highlight the importance of elucidating mechanisms involved in early cortical pathology,” according to the investigators.

Following Patients With Relapsing-Remitting MS

Among patients with relapsing-remitting MS, a high frequency of early relapses is associated with increased risk of developing severe disability, which suggests that early biologic mechanisms influence long-term disease evolution. Antonio Scalfari, MD, PhD, a consultant neurologist at Imperial College Healthcare in London, and colleagues sought to investigate the relationship between early cortical pathology, early relapses, and the risk of converting to secondary progressive MS.

Dr. Scalfari and colleagues examined 219 patients with relapsing-remitting MS. Participants had one (n = 116), two (n = 53), or three or more (n = 50) relapses during the first two years. Follow-up lasted for a mean of 7.9 years. The researchers assessed the number of cortical lesions and white matter lesions and the rate of cortical thinning using 3D double inversion recovery, 3D T1-weighted imaging, and Freesurfer analysis.

Cortical Lesions Predicted Cortical Thinning

During the observation period, 59 (27%) patients converted to secondary progressive MS in a mean of 6.1 years. At disease onset, the investigators detected 674 cortical lesions in 166 (76%) patients. A larger number of cortical lesions was associated with a significantly higher risk of secondary progressive MS. The hazard ratios (HR) for secondary progressive MS were 2.16 for patients with two lesions, 4.79 for patients with five lesions, and 12.3 for patients with seven lesions. A large number of cortical lesions also was associated with shorter latency to secondary progressive MS and a faster rate of global cortical thinning. The mean loss per year was 0.93% for patients with no lesions, 0.99% for patients with one to three lesions, 1.13% for patients with four to six lesions, and 1.33% for patients with seven or more lesions. In the group with no cortical lesions (n = 53), no patients entered the secondary progressive phase, and four reached an Expanded Disability Status Scale score of 4.

Patients with a high number of early relapses, compared with those with low and moderate numbers, had a larger volume of white matter lesions and cortical lesions at onset. The mean volumes of cortical lesions were 181.6 mm³, 386.8 mm³, and 544.0 mm³ for patients with one, two, and three or more early relapses, respectively. Patients with a high number of early relapses also accrued more cortical lesions (mean cortical lesion volumes were 118.8 mm³, 138.8 mm³, and 790.5 mm³ for patients with one, two, and three or more early relapses, respectively), had a faster rate of cortical atrophy (mean loss/year was 0.47%, 0.79%, and 0.94% for patients with one, two, and three or more early relapses, respectively), and entered the secondary progressive phase more rapidly.

In the multivariate model, older age at onset (HR, 1.97), a larger baseline cortical lesion (HR, 2.21) and white matter lesion (HR, 1.32) volume, early changes of global cortical thickness (HR, 1.36), and three or more early relapses (HR, 6.08) independently predicted a higher probability of secondary progressive MS.

BERLIN—Data from the Big Multiple Sclerosis Data (BMSD) Network indicate that the optimal time to start disease-modifying therapy in patients with multiple sclerosis (MS) to prevent the long-term accumulation of disability is within six months of disease onset. This finding was presented by Pietro Iaffaldano, MD, and colleagues at ECTRIMS 2018. Dr. Iaffaldano is Assistant Professor of Neurology at the University of Bari, Italy.

Many randomized clinical trials support the early start of disease-modifying therapies in MS. However, there is still an ongoing discussion on the optimal timing of treatment. For insight into this and other questions, the Danish, Italian, and Swedish national MS registries, MSBase, and the OFSEP of France pooled data for specific research projects in the BMSD Network. One question they sought to answer with this large, real-world data set was the optimal time to start disease-modifying therapy to prevent long-term disability accumulation in MS.

A cohort of patients with relapsing-remitting MS who had 10 or more years of follow-up, three or more years of cumulative disease-modifying therapy exposure, and three or more Expanded Disability Status Scale (EDSS) score evaluations was selected from the pooled cohort of the BMSD Network. The researchers conducted a set of pairwise (1:1) propensity score matching analyses with 10 different cut-offs for early versus delayed treatment (> 0.5 year up to > 5.0 years, using 0.5-year intervals) to allow an unbiased comparison between groups. The logistic model to predict propensity score included the following covariates: age at onset of the disease, sex, baseline EDSS, number of relapses in the two years before disease-modifying therapy start, number of EDSS evaluations, decade of birth, and registry source. To estimate the risk of reaching 12 months-confirmed EDSS progression (EDSSpr), a set of Cox models, adjusted for disease duration and relapses after disease-modifying therapy start as time-dependent covariates, was calculated.

A cohort of 11,871 patients with relapsing-remitting MS (71.0% female) was retrieved from the pooled BMSD Network database. The median (interquartile range) age at onset was 27.7 (22.3–34.6), median follow-up was 13.2 (11.4–15.4) years, and median time to the first disease-modifying therapy start was 3.8 (1.5–8.5) years. During the follow-up, an EDSSpr was reached by 4,138 (34.9%) patients. The lowest hazard ratio (HR) with relative 95% confidence interval (CI) for the propensity score matched models was obtained by a cutoff of treatment start within six months from disease onset (n = 873 per group). Early treatment significantly reduced the risk of reaching an EDSSpr (HR, 0.72 ). All subsequent comparisons between early and delayed treatment were not statistically significant.

This project was supported by Biogen International (Zug, Switzerland) on the basis of a sponsored research agreement with the BMSD Network.

BERLIN—Data from the Big Multiple Sclerosis Data (BMSD) Network indicate that the optimal time to start disease-modifying therapy in patients with multiple sclerosis (MS) to prevent the long-term accumulation of disability is within six months of disease onset. This finding was presented by Pietro Iaffaldano, MD, and colleagues at ECTRIMS 2018. Dr. Iaffaldano is Assistant Professor of Neurology at the University of Bari, Italy.

Many randomized clinical trials support the early start of disease-modifying therapies in MS. However, there is still an ongoing discussion on the optimal timing of treatment. For insight into this and other questions, the Danish, Italian, and Swedish national MS registries, MSBase, and the OFSEP of France pooled data for specific research projects in the BMSD Network. One question they sought to answer with this large, real-world data set was the optimal time to start disease-modifying therapy to prevent long-term disability accumulation in MS.

A cohort of patients with relapsing-remitting MS who had 10 or more years of follow-up, three or more years of cumulative disease-modifying therapy exposure, and three or more Expanded Disability Status Scale (EDSS) score evaluations was selected from the pooled cohort of the BMSD Network. The researchers conducted a set of pairwise (1:1) propensity score matching analyses with 10 different cut-offs for early versus delayed treatment (> 0.5 year up to > 5.0 years, using 0.5-year intervals) to allow an unbiased comparison between groups. The logistic model to predict propensity score included the following covariates: age at onset of the disease, sex, baseline EDSS, number of relapses in the two years before disease-modifying therapy start, number of EDSS evaluations, decade of birth, and registry source. To estimate the risk of reaching 12 months-confirmed EDSS progression (EDSSpr), a set of Cox models, adjusted for disease duration and relapses after disease-modifying therapy start as time-dependent covariates, was calculated.

A cohort of 11,871 patients with relapsing-remitting MS (71.0% female) was retrieved from the pooled BMSD Network database. The median (interquartile range) age at onset was 27.7 (22.3–34.6), median follow-up was 13.2 (11.4–15.4) years, and median time to the first disease-modifying therapy start was 3.8 (1.5–8.5) years. During the follow-up, an EDSSpr was reached by 4,138 (34.9%) patients. The lowest hazard ratio (HR) with relative 95% confidence interval (CI) for the propensity score matched models was obtained by a cutoff of treatment start within six months from disease onset (n = 873 per group). Early treatment significantly reduced the risk of reaching an EDSSpr (HR, 0.72 ). All subsequent comparisons between early and delayed treatment were not statistically significant.

This project was supported by Biogen International (Zug, Switzerland) on the basis of a sponsored research agreement with the BMSD Network.

BERLIN—Data from the Big Multiple Sclerosis Data (BMSD) Network indicate that the optimal time to start disease-modifying therapy in patients with multiple sclerosis (MS) to prevent the long-term accumulation of disability is within six months of disease onset. This finding was presented by Pietro Iaffaldano, MD, and colleagues at ECTRIMS 2018. Dr. Iaffaldano is Assistant Professor of Neurology at the University of Bari, Italy.

Many randomized clinical trials support the early start of disease-modifying therapies in MS. However, there is still an ongoing discussion on the optimal timing of treatment. For insight into this and other questions, the Danish, Italian, and Swedish national MS registries, MSBase, and the OFSEP of France pooled data for specific research projects in the BMSD Network. One question they sought to answer with this large, real-world data set was the optimal time to start disease-modifying therapy to prevent long-term disability accumulation in MS.

A cohort of patients with relapsing-remitting MS who had 10 or more years of follow-up, three or more years of cumulative disease-modifying therapy exposure, and three or more Expanded Disability Status Scale (EDSS) score evaluations was selected from the pooled cohort of the BMSD Network. The researchers conducted a set of pairwise (1:1) propensity score matching analyses with 10 different cut-offs for early versus delayed treatment (> 0.5 year up to > 5.0 years, using 0.5-year intervals) to allow an unbiased comparison between groups. The logistic model to predict propensity score included the following covariates: age at onset of the disease, sex, baseline EDSS, number of relapses in the two years before disease-modifying therapy start, number of EDSS evaluations, decade of birth, and registry source. To estimate the risk of reaching 12 months-confirmed EDSS progression (EDSSpr), a set of Cox models, adjusted for disease duration and relapses after disease-modifying therapy start as time-dependent covariates, was calculated.

A cohort of 11,871 patients with relapsing-remitting MS (71.0% female) was retrieved from the pooled BMSD Network database. The median (interquartile range) age at onset was 27.7 (22.3–34.6), median follow-up was 13.2 (11.4–15.4) years, and median time to the first disease-modifying therapy start was 3.8 (1.5–8.5) years. During the follow-up, an EDSSpr was reached by 4,138 (34.9%) patients. The lowest hazard ratio (HR) with relative 95% confidence interval (CI) for the propensity score matched models was obtained by a cutoff of treatment start within six months from disease onset (n = 873 per group). Early treatment significantly reduced the risk of reaching an EDSSpr (HR, 0.72 ). All subsequent comparisons between early and delayed treatment were not statistically significant.

This project was supported by Biogen International (Zug, Switzerland) on the basis of a sponsored research agreement with the BMSD Network.

BERLIN—Serum neurofilament light chain (sNfL) levels are clinically relevant, and data suggest cut points to enable disease severity stratification and treatment monitoring in patients with relapsing-remitting multiple sclerosis (MS), according to research described at ECTRIMS 2018.

Various investigations have indicated that sNfL is associated with disease activity and predicts long-term clinical and imaging outcomes in patients with relapsing-remitting MS. Disease-modifying treatments (DMTs) reduce sNfL levels in these patients. “The integration of sNfL into clinical practice will require a standardized, validated assay and defined, clinically meaningful cut points validated with real-world data,” said Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins Medicine in Baltimore, and colleagues.

Dr. Calabresi and colleagues conducted a study to define the sNfL levels relevant to disease severity stratification and treatment monitoring in patients with relapsing-remitting MS using samples and data from phase III clinical studies supported by Biogen. They measured sNfL with a single-molecule array Advantage kit or laboratory method in serial samples from more than 1,000 patients enrolled in four studies.

In the ADVANCE trial (which examined peginterferon beta-1a in 594 patients with relapsing-remitting MS), sNfL was measured at baseline, every three months until Year 2, and then every six months until Year 4. In the CHAMPS trial (which analyzed interferon beta 1a in 319 patients with clinically isolated syndrome), sNfL was measured at baseline and Week 48. In the MSCRG study (which examined interferon beta 1a in 164 patients with relapsing-remitting MS), sNfL was measured at Years 3 and 4. In SENTINEL (which examined natalizumab in 122 patients with relapsing-remitting MS), sNfL was measured at baseline and Week 96. Statistical analyses included Spearman correlation, analysis of variance, chi-squared test, Kaplan-Meier analysis, and multivariate logistic regression.

Baseline sNfL levels were associated with the number of enhancing lesions and accumulation of new T2 lesions over time. Patients with no evident disease activity had consistently low sNfL levels, but those with active disease, especially with high brain atrophy rates, had elevated sNfL levels. Dr. Calabresi’s group found that an sNfL level greater than 16 pg/mL indicated a high probability of disease activity over the following year (positive predictive values of 92% and 95% in test and verification cohorts, respectively). Using the average of sNfL levels at baseline and Months 3 and 6 further improved the positive predictive value. Similarly, an sNfL level greater than 16 pg/mL was associated long-term with worse clinical and imaging outcomes, including progression of Expanded Disability Status Scale score (12 years), increase in T2 lesion volume (10 years), and brain atrophy (five years). DMTs lowered sNfL levels. Natalizumab reduced sNfL below 16 pg/mL in 96% of patients.

The study was sponsored by Biogen.

BERLIN—Serum neurofilament light chain (sNfL) levels are clinically relevant, and data suggest cut points to enable disease severity stratification and treatment monitoring in patients with relapsing-remitting multiple sclerosis (MS), according to research described at ECTRIMS 2018.

Various investigations have indicated that sNfL is associated with disease activity and predicts long-term clinical and imaging outcomes in patients with relapsing-remitting MS. Disease-modifying treatments (DMTs) reduce sNfL levels in these patients. “The integration of sNfL into clinical practice will require a standardized, validated assay and defined, clinically meaningful cut points validated with real-world data,” said Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins Medicine in Baltimore, and colleagues.

Dr. Calabresi and colleagues conducted a study to define the sNfL levels relevant to disease severity stratification and treatment monitoring in patients with relapsing-remitting MS using samples and data from phase III clinical studies supported by Biogen. They measured sNfL with a single-molecule array Advantage kit or laboratory method in serial samples from more than 1,000 patients enrolled in four studies.

In the ADVANCE trial (which examined peginterferon beta-1a in 594 patients with relapsing-remitting MS), sNfL was measured at baseline, every three months until Year 2, and then every six months until Year 4. In the CHAMPS trial (which analyzed interferon beta 1a in 319 patients with clinically isolated syndrome), sNfL was measured at baseline and Week 48. In the MSCRG study (which examined interferon beta 1a in 164 patients with relapsing-remitting MS), sNfL was measured at Years 3 and 4. In SENTINEL (which examined natalizumab in 122 patients with relapsing-remitting MS), sNfL was measured at baseline and Week 96. Statistical analyses included Spearman correlation, analysis of variance, chi-squared test, Kaplan-Meier analysis, and multivariate logistic regression.

Baseline sNfL levels were associated with the number of enhancing lesions and accumulation of new T2 lesions over time. Patients with no evident disease activity had consistently low sNfL levels, but those with active disease, especially with high brain atrophy rates, had elevated sNfL levels. Dr. Calabresi’s group found that an sNfL level greater than 16 pg/mL indicated a high probability of disease activity over the following year (positive predictive values of 92% and 95% in test and verification cohorts, respectively). Using the average of sNfL levels at baseline and Months 3 and 6 further improved the positive predictive value. Similarly, an sNfL level greater than 16 pg/mL was associated long-term with worse clinical and imaging outcomes, including progression of Expanded Disability Status Scale score (12 years), increase in T2 lesion volume (10 years), and brain atrophy (five years). DMTs lowered sNfL levels. Natalizumab reduced sNfL below 16 pg/mL in 96% of patients.

The study was sponsored by Biogen.

BERLIN—Serum neurofilament light chain (sNfL) levels are clinically relevant, and data suggest cut points to enable disease severity stratification and treatment monitoring in patients with relapsing-remitting multiple sclerosis (MS), according to research described at ECTRIMS 2018.

Various investigations have indicated that sNfL is associated with disease activity and predicts long-term clinical and imaging outcomes in patients with relapsing-remitting MS. Disease-modifying treatments (DMTs) reduce sNfL levels in these patients. “The integration of sNfL into clinical practice will require a standardized, validated assay and defined, clinically meaningful cut points validated with real-world data,” said Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins Medicine in Baltimore, and colleagues.

Dr. Calabresi and colleagues conducted a study to define the sNfL levels relevant to disease severity stratification and treatment monitoring in patients with relapsing-remitting MS using samples and data from phase III clinical studies supported by Biogen. They measured sNfL with a single-molecule array Advantage kit or laboratory method in serial samples from more than 1,000 patients enrolled in four studies.

In the ADVANCE trial (which examined peginterferon beta-1a in 594 patients with relapsing-remitting MS), sNfL was measured at baseline, every three months until Year 2, and then every six months until Year 4. In the CHAMPS trial (which analyzed interferon beta 1a in 319 patients with clinically isolated syndrome), sNfL was measured at baseline and Week 48. In the MSCRG study (which examined interferon beta 1a in 164 patients with relapsing-remitting MS), sNfL was measured at Years 3 and 4. In SENTINEL (which examined natalizumab in 122 patients with relapsing-remitting MS), sNfL was measured at baseline and Week 96. Statistical analyses included Spearman correlation, analysis of variance, chi-squared test, Kaplan-Meier analysis, and multivariate logistic regression.

Baseline sNfL levels were associated with the number of enhancing lesions and accumulation of new T2 lesions over time. Patients with no evident disease activity had consistently low sNfL levels, but those with active disease, especially with high brain atrophy rates, had elevated sNfL levels. Dr. Calabresi’s group found that an sNfL level greater than 16 pg/mL indicated a high probability of disease activity over the following year (positive predictive values of 92% and 95% in test and verification cohorts, respectively). Using the average of sNfL levels at baseline and Months 3 and 6 further improved the positive predictive value. Similarly, an sNfL level greater than 16 pg/mL was associated long-term with worse clinical and imaging outcomes, including progression of Expanded Disability Status Scale score (12 years), increase in T2 lesion volume (10 years), and brain atrophy (five years). DMTs lowered sNfL levels. Natalizumab reduced sNfL below 16 pg/mL in 96% of patients.

The study was sponsored by Biogen.