ECTRIMS 2016

LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.

Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.

LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.

Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.

LONDON – Severe vitamin D deficiency and current smoking predicted accumulated disability in patients with clinically isolated syndrome, which can be a precursor to the development of multiple sclerosis.

Prospectively collected data from the ongoing Barcelona clinically isolated syndrome (CIS) cohort, which includes more than 1,000 patients with CIS, showed that patients with a serum vitamin D below 8.0 ng/mL (9% of 503 patient samples) had more than double the risk for accumulated disability when compared with those who had higher vitamin D levels. The hazard ratio for disability with severely low vitamin D levels was 2.3 (P = .049) in an analysis adjusted for the potential confounding factors of patients’ sex and age, the number of baseline T2 lesions, receipt of disease-modifying treatment, CIS topography, and oligoclonal bands. Disability accumulation was defined as an Expanded Disability Status Scale score of 3.0 or more.

LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.

The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.

LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.

The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.

LONDON – Contrary to expectation of a neuroprotective benefit, fluoxetine does not slow down the progressive phase of multiple sclerosis, according to the results of a randomized, double-blind, multicenter trial.

The first results of the FLUOX-PMS trial, reported by Melissa Cambron, MD, of University Hospital Brussels (Belgium), showed no statistically significant difference between fluoxetine and placebo for improving the primary endpoint of the time to confirmed disease progression.

LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.

LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.

LONDON – Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis than in healthy subjects in a proof-of-concept study reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 vs. 12.5 pg/mL, respectively (P less than .0001), and were also found to be higher in relapsing-remitting multiple sclerosis (RRMS) patients with greater disease activity seen on MRI.

LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.

In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.

The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).

“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.

“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.

Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.

Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.

Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.

The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).

There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).

However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.

The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.

“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.

Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.

LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.

In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.

The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).

“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.

“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.

Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.

Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.

Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.

The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).

There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).

However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.

The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.

“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.

Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.

LONDON – Patients with relapsing-remitting multiple sclerosis reported that their ability to walk was significantly improved following 6 months of treatment with extended-release dalfampridine – compared with patients on placebo – in a double-blind, randomized trial.

In the ENHANCE study, 43.2% of the 315 patients treated with extended-release dalfampridine (dalfampridine-ER; Ampyra) and 33.6% of the 318 who were given placebo achieved a clinically meaningful improvement of 8 or more points on the 12-item MS Walking Scale (MSWS-12) measured at week 24.

The odds ratio (OR) was 1.61, highlighting a significant difference between the two study arms (P = .006).

“This is one of the only studies to use a PRO [patient-reported outcome] as the primary outcome and to use an a priori threshold of clinical meaningfulness,” said Jeremy Hobart, MD, of Plymouth Hospitals NHS Trust (England), who reported the study’s findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. This is an important, and challenging, development in MS trials, he added.

“We are all aware that walking impairments are one of the hallmarks of multiple sclerosis,” Dr. Hobart said, adding that it affects the “vast majority” of patients.

Dalfampridine-ER, which is known as prolonged-release fampridine in Europe, is the only therapy licensed to improve walking in MS, he observed. The pivotal studies that led to the drug’s approval, however, were of relatively short duration and the ENHANCE study was conducted to answer questions that have been raised about the durability of its effect on patients’ mobility.

Patients in ENHANCE received either dalfampridine-ER at a twice-daily dose of 10 mg or placebo for 24 weeks. The mean age of patients in each group was 49 and 48 years, respectively, and 59% and 57% of recruited patients in each arm were female. Patients were stratified according to their baseline Expanded Disability Status Scale (EDSS) score, with 78% and 77% in the dalfampridine-ER and placebo groups having a score of 6 or less.

Dr. Hobart noted that the mean change in MSWS-12 scores over time and an analysis of the cumulative proportion of responders at any particular threshold score on the MWSW-12 showed a clear benefit of dalfampridine-ER treatment over placebo.

The study investigators also assessed patients’ balance via the Timed Up and Go (TUG) test, with a benefit threshold set at obtaining at least a 15% or more improvement at 24 weeks. Significantly more dalfampridine-ER–treated than placebo-treated patients achieved this threshold (43.4% vs. 34.7%; OR, 1.46; P = .03).

There was a significant improvement between the two study arms on the 29-item physical scale of the Multiple Sclerosis Impact Scale (P less than .001).

However, there was no change seen in upper extremity function, with similar mean changes in the Berg Balance Scale score and the ABILHAND score at 24 weeks. The mean baseline scores for both of these measures were high, Dr. Hobart observed, which probably affected the findings. That said, patients with a baseline EDSS of 6 or higher had greater improvement in ABILHAND scores if they had received dalfampridine-ER, compared with placebo, but the difference was not statistically significant.

The safety profile was consistent with what has been seen in other trials, Dr. Hobart said, and there were no new safety concerns raised.

“The findings from ENHANCE expand and tend to ... confirm the favorable risk-benefit profile established in prior pivotal trials,” he said.

Biogen sponsored the study. Dr. Hobart disclosed receiving fees, honoraria, and research support from Biogen, Acorda, Genzyme, Global Blood Therapeutics, Merck Serono, Novartis, Tigercat, and Vanita.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Primary progressive MS is characterized by steadily increasing, objectively documented neurologic dysfunction or disability without recovery, although patients may have fluctuations and phases of stability.

Primary progressive MS remains a severely disabling condition with high unmet medical need. Investigators believe that B cells contribute to the pathogenesis of MS, including primary progressive MS. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20⁺ B cells, showed superior efficacy and favorable safety, compared with placebo, in the phase III ORATORIO study in patients with primary progressive MS.

Xavier Montalban, MD, PhD, Chair of the Department of Neurology-Neuroimmunology and Director of the Multiple Sclerosis Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, and colleagues sought to assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with NEP in the ORATORIO study.

In all, 732 patients were randomized (2:1) to receive 600 mg of ocrelizumab as two 300-mg IV infusions 14 days apart, or placebo every 24 weeks for at least 120 weeks until a prespecified number of 12-week confirmed disability progression events (as measured by Expanded Disability Status Scale score) occurred. Patients with NEP were defined as having no 12-week confirmed disability progression, and no 12-week confirmed progression of 20% or more on the timed 25-foot walk test and on the nine-hole peg test. A total of 230 placebo-treated patients and 461 ocrelizumab-treated patients were evaluable in this exploratory analysis of the ORATORIO trial.

Compared with placebo, ocrelizumab significantly increased the proportion of patients with NEP at Week 120. The relative risk of NEP for ocrelizumab versus placebo was 1.47. The proportions of ocrelizumab- and placebo-treated patients with NEP up to Week 120 were 42.7% and 29.1%, respectively. This result represents a 47% relative increase in the ocrelizumab group. The proportions of ocrelizumab- and placebo-treated patients with NEP for the individual components of NEP up to Week 120 were 68.5% and 63.0%, respectively, for 12-week confirmed disability progression; 51.0% and 38.7%, respectively, for the timed 25-foot walk test; and 82.2% and 71.3%, respectively for the nine-hole peg test.

The study was sponsored by F. Hoffmann-La Roche.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

Spasticity is common in MS and is associated with significant morbidity. The standard treatment is oral administration of baclofen, a γ-aminobutyric acid-b (GABA-b) receptor agonist. Baclofen is a racemic mixture, and its efficacy is thought to result from the R-enantiomer (arbaclofen). Therapeutic doses of baclofen can cause CNS side effects, decreased adherence, and decreased tolerability. Arbaclofen extended-release tablets potentially could reduce dosing frequency and adverse events.

Daniel Kantor, MD, a neurologist from Coconut Creek, Florida, and colleagues conducted a multicenter, randomized, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen extended-release tablets to those of placebo and baclofen over 12 weeks of treatment in patients with spasticity due to MS. Participants were randomized to receive 20 mg of arbaclofen bid, 20 mg of baclofen tablets qid, or matching placebo. The dose was titrated over four weeks, followed by a 12-week maintenance period. The primary end points were the mean changes in Total Numeric-transformed Modified Ashworth Scale (TNmAS) and Clinician Global Impression of Change (CGIC) at the end of the maintenance period.

Of 354 randomized participants, 59.0% had relapsing-remitting MS and 36.7% had secondary progressive MS. The average baseline TNmAS score was 7.78. Mean changes in TNmAS and CGIC were significantly greater for patients receiving arbaclofen, compared with patients receiving placebo. The researchers observed a greater difference in CGIC between arbaclofen and placebo, compared with that between baclofen and placebo, perhaps because of improved tolerability of arbaclofen, compared with baclofen. Differences between arbaclofen and baclofen were not statistically significant. MS Spasticity Scale (MSSS-88) showed a statistically significant improvement among patients receiving arbaclofen, compared with those receiving placebo. Epworth Sleepiness Scale (ESS) showed a statistically significant increase in sleepiness in the baclofen group, but not in the arbaclofen group, compared with placebo. Drowsiness and dizziness were less frequent in the arbaclofen group, compared with baclofen.

The study was supported by Osmotica Pharmaceutical.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON – Siponimod delayed disability progression in patients with secondary progressive multiple sclerosis, according to top-line findings from the phase III EXPAND study.

Siponimod reduced the primary endpoint of the time to 3-month confirmed disease progression (CDP) assessed via the Expanded Disability Status Scale (EDSS) by 21%, compared with placebo (P = .013).

“It is reassuring that this primary outcome is supported by an important secondary outcome of the time to CDP at 6 months,” presenting author Ludwig Kappos, MD, of University Hospital Basel (Switzerland), said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He reported that a 26% reduction in the 6-month CDP was also observed comparing the active and placebo treatments (P = .006) in the multicenter, randomized, double-blind trial that involved 1,646 patients “with the whole spectrum” of secondary progressive multiple sclerosis (SPMS).

The findings build on those of the phase II BOLD study in patients with relapsing-remitting MS (RRMS) (Lancet Neurol. 2013;12[8]:756-67) and showed a reduction in relapse rates and a reduction in the number of brain lesions seen on MRI scans for siponimod, compared with placebo.

Recently reported data from the 24-month extension of the BOLD phase II trial (JAMA Neurol. 2016;73[9]:1089-98) also showed that disease activity was low in patients treated with siponimod, and that there were no new safety signals. Dose reduction during initiation mitigated cardiac adverse effects, an approach that was also used successfully in the phase III study.

Siponimod is a once-daily oral treatment being developed by Novartis for the treatment of MS. Like fingolimod (Gilenya), which is licensed for the treatment of RRMS, siponimod is a selective sphingosine 1-phosphate receptor (S1P) modulator. Unlike fingolimod, which targets S1P subtypes 1, 3, 4, and 5, siponimod only targets the S1P 1 and 5 subtypes.

Fingolimod is also known to cause temporary changes in heart rate, heartbeat, and blood pressure, which necessitates early electrocardiographic monitoring during the first 6 hours when the drug is first given. At the present time, it doesn’t seem that siponimod will have unwanted cardiac effects, but longer-term follow-up data are needed.

“Adverse events were as you would expect with an S1P receptor modulator,” Dr. Kappos said, noting that there was nothing new. Overall, any adverse event occurred in 88% of actively-treated and 81% of placebo-treated patients. The rate of serious adverse events was similar in the siponimod (3.8%) and placebo (3.7%) arms, and a similar percentage of patients were reported to have infections (48% and 49%, respectively).

Analysis of all the various secondary endpoints is still ongoing; Dr. Kappos noted that the primary endpoint data had just recently become available. Some initial findings, however, show benefit for siponimod over placebo.

The change in T2 lesion volume from baseline to both 12 and 24 months was significantly less with siponimod than with placebo, at a 79.1% lower average change (P less than .0001).

The annualized relapse rate was reduced by 55% with the active treatment versus placebo, and there was less percent change in brain volume with active therapy versus placebo from baseline to 12 and 24 months’ follow-up (23.4% lower average change, P = .0002).

The time to 3-month confirmed worsening by 20% or more from baseline in the timed 25-foot walk test was reduced by 6.2%. Although not significant, the trend was “in the right direction,” Dr. Kappos said.

The mean age of recruited patients was 48 years, with an average duration of MS of 16-17 years, and just under 4 years since their conversion to SPMS. Baseline EDSS was a mean of 5.4, around 35%-37% had one or more relapses in the 2 years before screening, and 20% had gadolinium-enhancing lesions at baseline.

A variety of predefined subgroup analyses showed a benefit for siponimod over placebo. These included analyses looking at the effect by the number of gadolinium-enhancing lesions at baseline, previous disease-modifying treatment, whether patients’ MS was rapidly progressing, whether patients’ disease was moderate or severe, the baseline EDSS, and the duration of MS since the first recognition of symptoms.

“What is the optimal patient population?” an audience member asked Dr. Kappos during the Q&A period following his presentation at the ECTRIMS meeting. He responded: “I think younger patients with the more active disease will certainly be the best candidates.” But, he added, it was reassuring to note that the drug seems to work equally well in all patient subtypes.

Novartis funded the study. Dr. Kappos disclosed that his institution has received financial support for research purposes from multiple MS drug manufacturers – including Novartis – and charitable organizations.

LONDON – New European guidelines on the pharmacologic treatment of multiple sclerosis consider all types of adult patients, including those with clinically isolated syndrome.

In addition to advocating early treatment in clinically isolated syndrome (CIS), the guidelines look at the treatment of relapsing-remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS), and give recommendations on monitoring therapy, what to do if a treatment needs to be stopped or switched, and how to treat in special situations such as pregnancy.

Developed jointly by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN), the guidelines are the first to formalize how best to use new disease-modifying drugs and strategies in Europe, based on current evidence.

“With several new drugs available in the past years, and others soon to come, this poses a major challenge to advice on a specific treatment for a specific patient,” said Susana Otero-Romero, MD, of the Centre d’Esclerosi Múltiple de Catalunya (CEMCAT) at Vall d’Hebron University Hospital in Barcelona.

Dr. Otero-Romero, who presented some general recommendations from the draft guidelines at the ECTRIMS annual congress, added that evidence-based guidance was needed and so ECTRIMS and EAN convened an expert panel in 2015 to review available data. The focus was on disease-modifying therapies approved by the European Medicines Agency.

The expert panel was chaired by the president of ECTRIMS, Xavier Montalbán, MD, of CEMCAT, and Ralf Gold, MD, of Ruhr-Universität Bochum in Germany, on behalf of the EAN, and included MS experts from across Europe, as well as patient representatives from groups such as the Multiple Sclerosis International Federation and the European Multiple Sclerosis Platform.

The panel followed the EAN’s recently issued framework for developing guidelines (Eur J Neurol. 2015 Dec;22[12]:1505-10) and Dr. Otero-Romero emphasized that the guidelines were built on the evidence base, using GRADE (Grading of Recommendations Assessment, Development Evaluation) methodology, to rate the quality and strength of each recommendation. Where no evidence was found, expert consensus was used.

Dr. Otero-Romero noted that an overall recommendation was that “the entire spectrum of disease-modifying drugs should only be prescribed in centers where there was the infrastructure to provide the proper monitoring of patients, comprehensive assessment, and detection of side effects and how to address them.”

That doesn’t mean patients need to be treated in specialist centers, Dr. Montalbán was keen to point out during discussions. It means that centers who prescribe the expanding range of MS drugs need to have a process to enable them to take good care of patients, monitor them, be aware of side effects, and have the expertise to be able to manage patients if side effects do occur.

“We looked specifically at the subpopulation of patients with CIS,” Dr. Otero-Romero noted, and said the panel decided that treatment with interferon or glatiramer acetate was the best option for CIS patients with an abnormal MRI scan who do not fulfill MS diagnostic criteria.

During discussion, a delegate queried why only injectable drugs were recommended when patients in this early phase of disease would probably be asking for oral treatment. Dr. Otero-Romero responded that this recommendation was based purely on the evidence available. “For now, this would only support starting on interferon or glatiramer acetate,” she said.

For patients with RRMS, defined as multiple relapses, MRI activity, or both, the recommendation is to offer early treatment with disease-modifying drugs. Which drug should be used is not specified, although the guidelines provide general advice on factors to consider when choosing a drug, including patient characteristics and comorbidities, disease severity and activity, the drug’s safety profile, and accessibility to the drug.

“There have not really been any head-to-head comparisons between drugs, so we do not have enough evidence to recommend one over another,” Dr. Otero-Romero said. “If you do not have good evidence you cannot really stratify the drugs and say ‘this one goes first, this one goes second,’ so we still need more evidence.”

For monitoring, consider MRI together with clinical measures. A reference brain MRI, taken within 6 months of starting disease-modifying treatment, is advocated, with a follow-up brain scan at 1 year, although the timing will need to be adjusted based on the drug treatment being used and the level of disease activity.

If there is a poor response to interferon or glatiramer acetate therapy or there is evidence of disease activity, the recommendation is to offer a more efficacious drug. If a highly efficacious drug then needs to be stopped for any reason, another highly efficacious drug should be considered. Factors to consider when switching include the degree of disease activity, which dictates how quickly the switch needs to be made, drugs’ respective half-lives and biological activity, and the potential for rebounding disease activity, particularly with natalizumab (Tysabri).

Although the expert panel has included a recommendation on the use of ocrelizumab for PPMS based on available phase III trial data, this is only if the drug is licensed for use by the EMA by the time the guidelines are published.

“We have agreed on our first set of recommendations. We will probably still work to refine some of these, and we expect to publish at the beginning of next year,” Dr. Otero-Romero said.

Providing independent comment in an interview, Samuel F. Hunter, MD, of the Advanced Neurosciences Institute in Nashville, Tenn., said that the European guidelines were of interest as there were no up-to-date guidelines on drug therapy for MS available in the United States.

While the American Academy of Neurology has produced practice guidelines on the use of disease-modifying therapies in MS (Neurology. 2002;58[2]:169-78) and issued specific guidance on natalizumab (Neurology. 2008;71[10]:766–73), these documents were published years ago. Five new therapies have appeared since then, Dr. Hunter said.

“Guidance is so far behind the advancement of therapy for MS, such that we don’t have any accepted guidelines. The current opinion from various groups is that all therapies should be available for all patients, according to physician advice,” Dr. Hunter said.

“People predominantly follow individual escalation of therapy efficacy guideline for the majority of patients, and people with very severe, fulminant relapses are relegated to higher-efficacy therapies,” he added.

The new European guidelines will influence what is happening in the United States, Dr. Hunter said, but there is such a diversity of interests among the large managed care organizations, the government, payers, pharmaceutical companies, and different academic centers, for example, that reaching a consensus will be difficult.

Dr. Otero-Romero did not declare any specific disclosures in relation to her presentation of the guidelines. Dr. Hunter did not have any disclosure relevant to his comments.

LONDON – New European guidelines on the pharmacologic treatment of multiple sclerosis consider all types of adult patients, including those with clinically isolated syndrome.

In addition to advocating early treatment in clinically isolated syndrome (CIS), the guidelines look at the treatment of relapsing-remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS), and give recommendations on monitoring therapy, what to do if a treatment needs to be stopped or switched, and how to treat in special situations such as pregnancy.

Developed jointly by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN), the guidelines are the first to formalize how best to use new disease-modifying drugs and strategies in Europe, based on current evidence.

“With several new drugs available in the past years, and others soon to come, this poses a major challenge to advice on a specific treatment for a specific patient,” said Susana Otero-Romero, MD, of the Centre d’Esclerosi Múltiple de Catalunya (CEMCAT) at Vall d’Hebron University Hospital in Barcelona.

Dr. Otero-Romero, who presented some general recommendations from the draft guidelines at the ECTRIMS annual congress, added that evidence-based guidance was needed and so ECTRIMS and EAN convened an expert panel in 2015 to review available data. The focus was on disease-modifying therapies approved by the European Medicines Agency.

The expert panel was chaired by the president of ECTRIMS, Xavier Montalbán, MD, of CEMCAT, and Ralf Gold, MD, of Ruhr-Universität Bochum in Germany, on behalf of the EAN, and included MS experts from across Europe, as well as patient representatives from groups such as the Multiple Sclerosis International Federation and the European Multiple Sclerosis Platform.

The panel followed the EAN’s recently issued framework for developing guidelines (Eur J Neurol. 2015 Dec;22[12]:1505-10) and Dr. Otero-Romero emphasized that the guidelines were built on the evidence base, using GRADE (Grading of Recommendations Assessment, Development Evaluation) methodology, to rate the quality and strength of each recommendation. Where no evidence was found, expert consensus was used.

Dr. Otero-Romero noted that an overall recommendation was that “the entire spectrum of disease-modifying drugs should only be prescribed in centers where there was the infrastructure to provide the proper monitoring of patients, comprehensive assessment, and detection of side effects and how to address them.”

That doesn’t mean patients need to be treated in specialist centers, Dr. Montalbán was keen to point out during discussions. It means that centers who prescribe the expanding range of MS drugs need to have a process to enable them to take good care of patients, monitor them, be aware of side effects, and have the expertise to be able to manage patients if side effects do occur.

“We looked specifically at the subpopulation of patients with CIS,” Dr. Otero-Romero noted, and said the panel decided that treatment with interferon or glatiramer acetate was the best option for CIS patients with an abnormal MRI scan who do not fulfill MS diagnostic criteria.

During discussion, a delegate queried why only injectable drugs were recommended when patients in this early phase of disease would probably be asking for oral treatment. Dr. Otero-Romero responded that this recommendation was based purely on the evidence available. “For now, this would only support starting on interferon or glatiramer acetate,” she said.

For patients with RRMS, defined as multiple relapses, MRI activity, or both, the recommendation is to offer early treatment with disease-modifying drugs. Which drug should be used is not specified, although the guidelines provide general advice on factors to consider when choosing a drug, including patient characteristics and comorbidities, disease severity and activity, the drug’s safety profile, and accessibility to the drug.

“There have not really been any head-to-head comparisons between drugs, so we do not have enough evidence to recommend one over another,” Dr. Otero-Romero said. “If you do not have good evidence you cannot really stratify the drugs and say ‘this one goes first, this one goes second,’ so we still need more evidence.”

For monitoring, consider MRI together with clinical measures. A reference brain MRI, taken within 6 months of starting disease-modifying treatment, is advocated, with a follow-up brain scan at 1 year, although the timing will need to be adjusted based on the drug treatment being used and the level of disease activity.

If there is a poor response to interferon or glatiramer acetate therapy or there is evidence of disease activity, the recommendation is to offer a more efficacious drug. If a highly efficacious drug then needs to be stopped for any reason, another highly efficacious drug should be considered. Factors to consider when switching include the degree of disease activity, which dictates how quickly the switch needs to be made, drugs’ respective half-lives and biological activity, and the potential for rebounding disease activity, particularly with natalizumab (Tysabri).

Although the expert panel has included a recommendation on the use of ocrelizumab for PPMS based on available phase III trial data, this is only if the drug is licensed for use by the EMA by the time the guidelines are published.

“We have agreed on our first set of recommendations. We will probably still work to refine some of these, and we expect to publish at the beginning of next year,” Dr. Otero-Romero said.

Providing independent comment in an interview, Samuel F. Hunter, MD, of the Advanced Neurosciences Institute in Nashville, Tenn., said that the European guidelines were of interest as there were no up-to-date guidelines on drug therapy for MS available in the United States.

While the American Academy of Neurology has produced practice guidelines on the use of disease-modifying therapies in MS (Neurology. 2002;58[2]:169-78) and issued specific guidance on natalizumab (Neurology. 2008;71[10]:766–73), these documents were published years ago. Five new therapies have appeared since then, Dr. Hunter said.

“Guidance is so far behind the advancement of therapy for MS, such that we don’t have any accepted guidelines. The current opinion from various groups is that all therapies should be available for all patients, according to physician advice,” Dr. Hunter said.

“People predominantly follow individual escalation of therapy efficacy guideline for the majority of patients, and people with very severe, fulminant relapses are relegated to higher-efficacy therapies,” he added.

The new European guidelines will influence what is happening in the United States, Dr. Hunter said, but there is such a diversity of interests among the large managed care organizations, the government, payers, pharmaceutical companies, and different academic centers, for example, that reaching a consensus will be difficult.

Dr. Otero-Romero did not declare any specific disclosures in relation to her presentation of the guidelines. Dr. Hunter did not have any disclosure relevant to his comments.

LONDON – New European guidelines on the pharmacologic treatment of multiple sclerosis consider all types of adult patients, including those with clinically isolated syndrome.

In addition to advocating early treatment in clinically isolated syndrome (CIS), the guidelines look at the treatment of relapsing-remitting multiple sclerosis (RRMS) and primary progressive MS (PPMS), and give recommendations on monitoring therapy, what to do if a treatment needs to be stopped or switched, and how to treat in special situations such as pregnancy.

Developed jointly by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN), the guidelines are the first to formalize how best to use new disease-modifying drugs and strategies in Europe, based on current evidence.

“With several new drugs available in the past years, and others soon to come, this poses a major challenge to advice on a specific treatment for a specific patient,” said Susana Otero-Romero, MD, of the Centre d’Esclerosi Múltiple de Catalunya (CEMCAT) at Vall d’Hebron University Hospital in Barcelona.

Dr. Otero-Romero, who presented some general recommendations from the draft guidelines at the ECTRIMS annual congress, added that evidence-based guidance was needed and so ECTRIMS and EAN convened an expert panel in 2015 to review available data. The focus was on disease-modifying therapies approved by the European Medicines Agency.

The expert panel was chaired by the president of ECTRIMS, Xavier Montalbán, MD, of CEMCAT, and Ralf Gold, MD, of Ruhr-Universität Bochum in Germany, on behalf of the EAN, and included MS experts from across Europe, as well as patient representatives from groups such as the Multiple Sclerosis International Federation and the European Multiple Sclerosis Platform.

The panel followed the EAN’s recently issued framework for developing guidelines (Eur J Neurol. 2015 Dec;22[12]:1505-10) and Dr. Otero-Romero emphasized that the guidelines were built on the evidence base, using GRADE (Grading of Recommendations Assessment, Development Evaluation) methodology, to rate the quality and strength of each recommendation. Where no evidence was found, expert consensus was used.

Dr. Otero-Romero noted that an overall recommendation was that “the entire spectrum of disease-modifying drugs should only be prescribed in centers where there was the infrastructure to provide the proper monitoring of patients, comprehensive assessment, and detection of side effects and how to address them.”

That doesn’t mean patients need to be treated in specialist centers, Dr. Montalbán was keen to point out during discussions. It means that centers who prescribe the expanding range of MS drugs need to have a process to enable them to take good care of patients, monitor them, be aware of side effects, and have the expertise to be able to manage patients if side effects do occur.

“We looked specifically at the subpopulation of patients with CIS,” Dr. Otero-Romero noted, and said the panel decided that treatment with interferon or glatiramer acetate was the best option for CIS patients with an abnormal MRI scan who do not fulfill MS diagnostic criteria.

During discussion, a delegate queried why only injectable drugs were recommended when patients in this early phase of disease would probably be asking for oral treatment. Dr. Otero-Romero responded that this recommendation was based purely on the evidence available. “For now, this would only support starting on interferon or glatiramer acetate,” she said.

For patients with RRMS, defined as multiple relapses, MRI activity, or both, the recommendation is to offer early treatment with disease-modifying drugs. Which drug should be used is not specified, although the guidelines provide general advice on factors to consider when choosing a drug, including patient characteristics and comorbidities, disease severity and activity, the drug’s safety profile, and accessibility to the drug.

“There have not really been any head-to-head comparisons between drugs, so we do not have enough evidence to recommend one over another,” Dr. Otero-Romero said. “If you do not have good evidence you cannot really stratify the drugs and say ‘this one goes first, this one goes second,’ so we still need more evidence.”

For monitoring, consider MRI together with clinical measures. A reference brain MRI, taken within 6 months of starting disease-modifying treatment, is advocated, with a follow-up brain scan at 1 year, although the timing will need to be adjusted based on the drug treatment being used and the level of disease activity.

If there is a poor response to interferon or glatiramer acetate therapy or there is evidence of disease activity, the recommendation is to offer a more efficacious drug. If a highly efficacious drug then needs to be stopped for any reason, another highly efficacious drug should be considered. Factors to consider when switching include the degree of disease activity, which dictates how quickly the switch needs to be made, drugs’ respective half-lives and biological activity, and the potential for rebounding disease activity, particularly with natalizumab (Tysabri).

Although the expert panel has included a recommendation on the use of ocrelizumab for PPMS based on available phase III trial data, this is only if the drug is licensed for use by the EMA by the time the guidelines are published.

“We have agreed on our first set of recommendations. We will probably still work to refine some of these, and we expect to publish at the beginning of next year,” Dr. Otero-Romero said.

Providing independent comment in an interview, Samuel F. Hunter, MD, of the Advanced Neurosciences Institute in Nashville, Tenn., said that the European guidelines were of interest as there were no up-to-date guidelines on drug therapy for MS available in the United States.

While the American Academy of Neurology has produced practice guidelines on the use of disease-modifying therapies in MS (Neurology. 2002;58[2]:169-78) and issued specific guidance on natalizumab (Neurology. 2008;71[10]:766–73), these documents were published years ago. Five new therapies have appeared since then, Dr. Hunter said.

“Guidance is so far behind the advancement of therapy for MS, such that we don’t have any accepted guidelines. The current opinion from various groups is that all therapies should be available for all patients, according to physician advice,” Dr. Hunter said.

“People predominantly follow individual escalation of therapy efficacy guideline for the majority of patients, and people with very severe, fulminant relapses are relegated to higher-efficacy therapies,” he added.

The new European guidelines will influence what is happening in the United States, Dr. Hunter said, but there is such a diversity of interests among the large managed care organizations, the government, payers, pharmaceutical companies, and different academic centers, for example, that reaching a consensus will be difficult.

Dr. Otero-Romero did not declare any specific disclosures in relation to her presentation of the guidelines. Dr. Hunter did not have any disclosure relevant to his comments.

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams