Multiple Sclerosis Hub

The concept that biotin, a water-soluble vitamin, could have a beneficial effect on the course of multiple sclerosis (MS) is biologically plausible. Biotin activates acetyl-CoA carboxylase, a potential rate-limiting enzyme in myelin synthesis, and has multiple other biochemical effects.

In a small consecutive pilot study in 2015 that was neither placebo-controlled, blinded, nor randomized, Sedel et al found a suggestion of high-dose biotin’s clinical efficacy in patients with progressive MS.

The follow-up study by Tourbah et al expanded and confirmed the clinical efficacy of high-dose biotin (in the form of MD1003) in progressive forms of MS. In contrast to the prior trial, this trial was a double-blind, placebo-controlled, randomized study of 154 patients treated with 300 mg of biotin or placebo daily for 48 weeks. The results indicated that 13.6% of 103 biotin-treated patients had improvement of disability, using change in Expanded Disability Status Scale score or Timed 25-Foot Walk from baseline, as compared with 51 placebo-treated patients. No serious side effects were reported.

Few, if any, studies have shown sustained clinical improvement in patients with progressive forms of MS to date. As is often the case, however, some patients with ostensibly progressive MS may have evidence of clinical relapses, as seen in the biotin trials, or subclinical MRI relapses, as seen by new T2 or enhancing lesions in other studies, that may respond transiently to corticosteroids or disease-modifying therapies.

The mechanism of action of biotin in progressive MS, if validated in other studies, is not well defined. Possibilities include remyelination, axonal regeneration, inhibition of free oxygen radicals, and other effects. Biotin’s efficacy probably is not due to immunosuppression, however.

The results of Dr. Tourbah’s study are consistent with previous animal and human data that indicate biotin’s excellent safety profile. For this reason, and in light of the lack of treatment efficacy in progressive MS, additional robust Phase III studies of biotin should be carried out in an attempt to corroborate and expand these findings. This effort should include a larger number of patients with a longer study duration and additional clinical, neuropsychologic, and MRI studies.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz
Professor of Neurology and Neurosciences
Rutgers, The State University of New Jersey
Newark, NJ

The concept that biotin, a water-soluble vitamin, could have a beneficial effect on the course of multiple sclerosis (MS) is biologically plausible. Biotin activates acetyl-CoA carboxylase, a potential rate-limiting enzyme in myelin synthesis, and has multiple other biochemical effects.

In a small consecutive pilot study in 2015 that was neither placebo-controlled, blinded, nor randomized, Sedel et al found a suggestion of high-dose biotin’s clinical efficacy in patients with progressive MS.

The follow-up study by Tourbah et al expanded and confirmed the clinical efficacy of high-dose biotin (in the form of MD1003) in progressive forms of MS. In contrast to the prior trial, this trial was a double-blind, placebo-controlled, randomized study of 154 patients treated with 300 mg of biotin or placebo daily for 48 weeks. The results indicated that 13.6% of 103 biotin-treated patients had improvement of disability, using change in Expanded Disability Status Scale score or Timed 25-Foot Walk from baseline, as compared with 51 placebo-treated patients. No serious side effects were reported.

Few, if any, studies have shown sustained clinical improvement in patients with progressive forms of MS to date. As is often the case, however, some patients with ostensibly progressive MS may have evidence of clinical relapses, as seen in the biotin trials, or subclinical MRI relapses, as seen by new T2 or enhancing lesions in other studies, that may respond transiently to corticosteroids or disease-modifying therapies.

The mechanism of action of biotin in progressive MS, if validated in other studies, is not well defined. Possibilities include remyelination, axonal regeneration, inhibition of free oxygen radicals, and other effects. Biotin’s efficacy probably is not due to immunosuppression, however.

The results of Dr. Tourbah’s study are consistent with previous animal and human data that indicate biotin’s excellent safety profile. For this reason, and in light of the lack of treatment efficacy in progressive MS, additional robust Phase III studies of biotin should be carried out in an attempt to corroborate and expand these findings. This effort should include a larger number of patients with a longer study duration and additional clinical, neuropsychologic, and MRI studies.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz
Professor of Neurology and Neurosciences
Rutgers, The State University of New Jersey
Newark, NJ

The concept that biotin, a water-soluble vitamin, could have a beneficial effect on the course of multiple sclerosis (MS) is biologically plausible. Biotin activates acetyl-CoA carboxylase, a potential rate-limiting enzyme in myelin synthesis, and has multiple other biochemical effects.

In a small consecutive pilot study in 2015 that was neither placebo-controlled, blinded, nor randomized, Sedel et al found a suggestion of high-dose biotin’s clinical efficacy in patients with progressive MS.

The follow-up study by Tourbah et al expanded and confirmed the clinical efficacy of high-dose biotin (in the form of MD1003) in progressive forms of MS. In contrast to the prior trial, this trial was a double-blind, placebo-controlled, randomized study of 154 patients treated with 300 mg of biotin or placebo daily for 48 weeks. The results indicated that 13.6% of 103 biotin-treated patients had improvement of disability, using change in Expanded Disability Status Scale score or Timed 25-Foot Walk from baseline, as compared with 51 placebo-treated patients. No serious side effects were reported.

Few, if any, studies have shown sustained clinical improvement in patients with progressive forms of MS to date. As is often the case, however, some patients with ostensibly progressive MS may have evidence of clinical relapses, as seen in the biotin trials, or subclinical MRI relapses, as seen by new T2 or enhancing lesions in other studies, that may respond transiently to corticosteroids or disease-modifying therapies.

The mechanism of action of biotin in progressive MS, if validated in other studies, is not well defined. Possibilities include remyelination, axonal regeneration, inhibition of free oxygen radicals, and other effects. Biotin’s efficacy probably is not due to immunosuppression, however.

The results of Dr. Tourbah’s study are consistent with previous animal and human data that indicate biotin’s excellent safety profile. For this reason, and in light of the lack of treatment efficacy in progressive MS, additional robust Phase III studies of biotin should be carried out in an attempt to corroborate and expand these findings. This effort should include a larger number of patients with a longer study duration and additional clinical, neuropsychologic, and MRI studies.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz
Professor of Neurology and Neurosciences
Rutgers, The State University of New Jersey
Newark, NJ

WASHINGTON, DC—Biotin may result in clinical improvement among patients with progressive multiple sclerosis (MS) and decrease the risk of progression, according to a study described at the 67th Annual Meeting of the American Academy of Neurology. The drug appears not to be associated with any significant adverse events.

Many MS therapies have reduced relapses effectively but have failed to produce significant and sustained reductions in disability. In an open-label study published in 2015, patients with progressive MS who received high doses of biotin had 22% clinical improvement, mainly in the Expanded Disability Status Scale (EDSS). Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France, and colleagues subsequently conducted a Phase III trial of MD1003, a highly concentrated pharmaceutical grade of biotin, at 16 MS reference centers.

Comparing MD1003 and Placebo
Eligible participants were between ages 18 and 75, had primary or secondary progressive MS, had an EDSS score between 4.5 and 7, and had disease progression within the previous two years, as measured by EDSS. Patients were excluded from the study if they had initiated a new disease-modifying therapy during the three months before enrollment or if they had received symptomatic treatment with fampridine within one month of enrollment.

The researchers screened 166 patients and included 154 of them in a two-to-one randomization. In all, 103 patients received daily 300-mg doses of MD1003, and 51 patients received placebo. Slightly more patients in the active arm had primary progressive MS, compared with the placebo group. Also, slightly more patients were taking fampridine in the placebo group, compared with the active group. The researchers noted no other differences between the treatment arms.

The study’s primary end point was the proportion of patients with improvement at month nine that was confirmed at month 12 using EDSS or the Timed 25-Foot Walk (T25FW), compared with baseline measures. EDSS improvement was defined as a decrease of at least one point for patients with a baseline EDSS between 4.5 and 5.5, and as a decrease of at least 0.5 points for patients with a baseline EDSS between 6 and 7. T25FW was considered improved if it decreased by at least 20%, compared with baseline.

Treated Patients Had Sustained Improvement
At the end of the study, 13 patients in the active arm had met the primary end point, compared with none of the patients in the placebo arm. The difference between groups was statistically significant. Twice as many patients met the primary end point with the EDSS, compared with the T25FW. The investigators found no major differences between the group of patients treated with MD1003 and the group of patients who met the primary end point.

A secondary analysis indicated that mean EDSS improved at the initial phase of the trial for participants in the treatment arm, and their improvement was sustained throughout the study. The placebo group had an initial improvement in mean EDSS, but EDSS worsened at all subsequent time points. After 12 months, the difference between the two groups in the mean change in EDSS was statistically significant.

In addition, 13.6% of patients in the placebo group had EDSS progression that was confirmed at two subsequent visits. In contrast, 4.2% of patients receiving MD1003 had progression at month nine that was confirmed at month 12. The difference between groups was not statistically significant, however. Nevertheless, the data indicate a 67% decrease in the risk of progression for patients receiving MD1003, compared with controls, said Dr. Tourbah. Similar trends were observed for the T25FW.

The researchers found no difference in adverse events between the treatment groups. Twice as many patients in the placebo group had relapses, compared with the active arm. High doses of biotin may interfere with immunoassays that use biotinylated antibodies or substrates, however, thus requiring patients and physicians to be informed adequately.

Biotin is a water-soluble coenzyme that is thought to promote myelination and enhance energy supply. “High doses of biotin may feed the Krebs cycle to increase adenosine triphosphate synthesis and energy production, thus possibly reversing virtual hypoxia and protecting neurons from degeneration,” said Dr. Tourbah.

—Erik Greb

WASHINGTON, DC—Biotin may result in clinical improvement among patients with progressive multiple sclerosis (MS) and decrease the risk of progression, according to a study described at the 67th Annual Meeting of the American Academy of Neurology. The drug appears not to be associated with any significant adverse events.

Many MS therapies have reduced relapses effectively but have failed to produce significant and sustained reductions in disability. In an open-label study published in 2015, patients with progressive MS who received high doses of biotin had 22% clinical improvement, mainly in the Expanded Disability Status Scale (EDSS). Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France, and colleagues subsequently conducted a Phase III trial of MD1003, a highly concentrated pharmaceutical grade of biotin, at 16 MS reference centers.

Comparing MD1003 and Placebo
Eligible participants were between ages 18 and 75, had primary or secondary progressive MS, had an EDSS score between 4.5 and 7, and had disease progression within the previous two years, as measured by EDSS. Patients were excluded from the study if they had initiated a new disease-modifying therapy during the three months before enrollment or if they had received symptomatic treatment with fampridine within one month of enrollment.

The researchers screened 166 patients and included 154 of them in a two-to-one randomization. In all, 103 patients received daily 300-mg doses of MD1003, and 51 patients received placebo. Slightly more patients in the active arm had primary progressive MS, compared with the placebo group. Also, slightly more patients were taking fampridine in the placebo group, compared with the active group. The researchers noted no other differences between the treatment arms.

The study’s primary end point was the proportion of patients with improvement at month nine that was confirmed at month 12 using EDSS or the Timed 25-Foot Walk (T25FW), compared with baseline measures. EDSS improvement was defined as a decrease of at least one point for patients with a baseline EDSS between 4.5 and 5.5, and as a decrease of at least 0.5 points for patients with a baseline EDSS between 6 and 7. T25FW was considered improved if it decreased by at least 20%, compared with baseline.

Treated Patients Had Sustained Improvement
At the end of the study, 13 patients in the active arm had met the primary end point, compared with none of the patients in the placebo arm. The difference between groups was statistically significant. Twice as many patients met the primary end point with the EDSS, compared with the T25FW. The investigators found no major differences between the group of patients treated with MD1003 and the group of patients who met the primary end point.

A secondary analysis indicated that mean EDSS improved at the initial phase of the trial for participants in the treatment arm, and their improvement was sustained throughout the study. The placebo group had an initial improvement in mean EDSS, but EDSS worsened at all subsequent time points. After 12 months, the difference between the two groups in the mean change in EDSS was statistically significant.

In addition, 13.6% of patients in the placebo group had EDSS progression that was confirmed at two subsequent visits. In contrast, 4.2% of patients receiving MD1003 had progression at month nine that was confirmed at month 12. The difference between groups was not statistically significant, however. Nevertheless, the data indicate a 67% decrease in the risk of progression for patients receiving MD1003, compared with controls, said Dr. Tourbah. Similar trends were observed for the T25FW.

The researchers found no difference in adverse events between the treatment groups. Twice as many patients in the placebo group had relapses, compared with the active arm. High doses of biotin may interfere with immunoassays that use biotinylated antibodies or substrates, however, thus requiring patients and physicians to be informed adequately.

Biotin is a water-soluble coenzyme that is thought to promote myelination and enhance energy supply. “High doses of biotin may feed the Krebs cycle to increase adenosine triphosphate synthesis and energy production, thus possibly reversing virtual hypoxia and protecting neurons from degeneration,” said Dr. Tourbah.

—Erik Greb

WASHINGTON, DC—Biotin may result in clinical improvement among patients with progressive multiple sclerosis (MS) and decrease the risk of progression, according to a study described at the 67th Annual Meeting of the American Academy of Neurology. The drug appears not to be associated with any significant adverse events.

Many MS therapies have reduced relapses effectively but have failed to produce significant and sustained reductions in disability. In an open-label study published in 2015, patients with progressive MS who received high doses of biotin had 22% clinical improvement, mainly in the Expanded Disability Status Scale (EDSS). Ayman Tourbah, MD, PhD, Professor of Neurology at Centre Hospitalier Universitaire in Reims, France, and colleagues subsequently conducted a Phase III trial of MD1003, a highly concentrated pharmaceutical grade of biotin, at 16 MS reference centers.

Comparing MD1003 and Placebo
Eligible participants were between ages 18 and 75, had primary or secondary progressive MS, had an EDSS score between 4.5 and 7, and had disease progression within the previous two years, as measured by EDSS. Patients were excluded from the study if they had initiated a new disease-modifying therapy during the three months before enrollment or if they had received symptomatic treatment with fampridine within one month of enrollment.

The researchers screened 166 patients and included 154 of them in a two-to-one randomization. In all, 103 patients received daily 300-mg doses of MD1003, and 51 patients received placebo. Slightly more patients in the active arm had primary progressive MS, compared with the placebo group. Also, slightly more patients were taking fampridine in the placebo group, compared with the active group. The researchers noted no other differences between the treatment arms.

The study’s primary end point was the proportion of patients with improvement at month nine that was confirmed at month 12 using EDSS or the Timed 25-Foot Walk (T25FW), compared with baseline measures. EDSS improvement was defined as a decrease of at least one point for patients with a baseline EDSS between 4.5 and 5.5, and as a decrease of at least 0.5 points for patients with a baseline EDSS between 6 and 7. T25FW was considered improved if it decreased by at least 20%, compared with baseline.

Treated Patients Had Sustained Improvement
At the end of the study, 13 patients in the active arm had met the primary end point, compared with none of the patients in the placebo arm. The difference between groups was statistically significant. Twice as many patients met the primary end point with the EDSS, compared with the T25FW. The investigators found no major differences between the group of patients treated with MD1003 and the group of patients who met the primary end point.

A secondary analysis indicated that mean EDSS improved at the initial phase of the trial for participants in the treatment arm, and their improvement was sustained throughout the study. The placebo group had an initial improvement in mean EDSS, but EDSS worsened at all subsequent time points. After 12 months, the difference between the two groups in the mean change in EDSS was statistically significant.

In addition, 13.6% of patients in the placebo group had EDSS progression that was confirmed at two subsequent visits. In contrast, 4.2% of patients receiving MD1003 had progression at month nine that was confirmed at month 12. The difference between groups was not statistically significant, however. Nevertheless, the data indicate a 67% decrease in the risk of progression for patients receiving MD1003, compared with controls, said Dr. Tourbah. Similar trends were observed for the T25FW.

The researchers found no difference in adverse events between the treatment groups. Twice as many patients in the placebo group had relapses, compared with the active arm. High doses of biotin may interfere with immunoassays that use biotinylated antibodies or substrates, however, thus requiring patients and physicians to be informed adequately.

Biotin is a water-soluble coenzyme that is thought to promote myelination and enhance energy supply. “High doses of biotin may feed the Krebs cycle to increase adenosine triphosphate synthesis and energy production, thus possibly reversing virtual hypoxia and protecting neurons from degeneration,” said Dr. Tourbah.

—Erik Greb

WASHINGTON, DC—Treatment with daclizumab high-yield process (DAC HYP), a first-in-class immunomodulator administered subcutaneously once per month, was significantly more effective on various outcomes in relapsing-remitting multiple sclerosis (MS) than was interferon (IFN) β-1a therapy, according to results from the international DECIDE study presented at the 67th Annual Meeting of the American Academy of Neurology.

The efficacy of DAC HYP was consistently superior to that of once-weekly intramuscular IFN β-1a “across key clinical, radiographic, and patient-reported MS outcome measures,” with a 45% reduction in the annualized relapse rate over the study’s treatment period of 96 to 144 weeks, said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel and of the DECIDE study’s advisory committee. DAC HYP “has the potential to be a new once-monthly treatment option for patients with relapsing MS,” he said.

Treatment with DAC HYP was associated with an increased risk of infections, cutaneous adverse effects, and hepatic enzyme abnormalities, which were “manageable with standard monitoring and medical interventions,” Dr. Kappos said.

DAC HYP is a humanized monoclonal antibody that selectively blocks the high-affinity interleukin-2 receptor subunit CD25, which is expressed at high levels on T cells that are abnormally activated in MS. The biological effects of CD25 blockade include the inhibition of activated T cell responses and “normalization of lymphoid tissue inducer cell numbers,” he said.

Reduction in Relapse Rate Was Highly Significant
The DECIDE phase III study randomized 919 patients to treatment with 150 mg of DAC HYP administered subcutaneously once every four weeks and 922 patients to treatment with 30 mg of IFN β-1a administered intramuscularly once per week. Mean age of the patients was 36 years, 68% were women, and they had been diagnosed with MS for a mean of five years. Patients in both groups had had a similar mean number of relapses within the previous year (between 0.7 and 0.8); 21% had highly active MS, and 41% had been on disease-modifying treatments previously. Their mean Expanded Disability Status Scale (EDSS) score was between 1.2 and 1.3. In both arms, approximately 30% of patients discontinued treatment. The percentage of patients that discontinued treatment because of adverse events was higher in the DAC HYP-treated group.

The annualized relapse rate—the study’s primary end point—was 0.393 among those on IFN β-1a, compared with 0.216 among those on DAC HYP, a 45% reduction that was highly statistically significant, Dr. Kappos said.

Secondary end points included the proportion of patients who remained relapse-free, which was higher among those on DAC HYP at various points during the study (eg, 73% vs 59% at week 96, and 67% vs 51% at week 144). The risk of relapse was reduced by 41%.

Other secondary end points were MRI-defined lesions at week 96. The number of new or newly enlarging T2 hyperintense lesions at that point was reduced by 54%, compared with IFN β-1a. There were similar reductions in new T1 black holes, which were reduced by 52%, and in gadolinium-enhancing lesions, which were reduced by 65%. There was a significant positive effect of treatment on brain volume over time, which was possible to detect because the study was so large, Dr. Kappos said.

At three months, the risk of progression was reduced by 16% among those on DAC HYP, compared with those on IFN β-1a, although the effect was not statistically significant. At six months, the risk was reduced by 27%. The proportion of patients on DAC HYP with a clinically meaningful worsening in patient-reported physical impact of MS (defined by at least a 7.5-point decrease on MSIS-29-PHYS) was reduced by 24%, compared with those on IFN β-1a. The reduction was not statistically significant.

Hepatic Abnormalities Were More Common in Daclizumab Patients
The incidence of any type of adverse event was 91% in both groups, and infections, cutaneous events, and hepatic abnormalities were more common among those treated with DAC HYP. Serious adverse events were higher among those on DAC HYP (24% vs 21%); when MS relapses were excluded, the rates were 15% and 10%. Treatment discontinuations due to an adverse event other than an MS relapse were 14% among those on DAC HYP, compared with 9% of those on IFN β-1a. There were five deaths, one in a patient on the study drug and four among those on the comparator.

The rate of infectious adverse events was higher among those on DAC HYP (65% vs 57%), as was the rate of serious infectious adverse events (4% vs 2%). Cutaneous events were more common among those on DAC HYP (37% vs 19%), as were serious cutaneous adverse events (2% vs less than 1%).

Hepatic abnormalities were more common among those on DAC HYP, but were reversible, Dr. Kappos said. The rate of aspartate aminotransferase/alanine aminotransferase (AST/ALT) greater than five times the upper limit of normal (ULN) was 6% among those on DAC HYP, compared with 3% among those on IFN β-1a. The rate of ALT greater than three times the ULN and total bilirubin more than twice the ULN was less than 1% in each group. There was one case in each group that met Hy’s law criteria, which are used to predict the potential of drugs to cause serious liver injury.

Biogen Idec and AbbVie Biotherapeutics funded the study.

—Elizabeth Mechcatie

WASHINGTON, DC—Treatment with daclizumab high-yield process (DAC HYP), a first-in-class immunomodulator administered subcutaneously once per month, was significantly more effective on various outcomes in relapsing-remitting multiple sclerosis (MS) than was interferon (IFN) β-1a therapy, according to results from the international DECIDE study presented at the 67th Annual Meeting of the American Academy of Neurology.

The efficacy of DAC HYP was consistently superior to that of once-weekly intramuscular IFN β-1a “across key clinical, radiographic, and patient-reported MS outcome measures,” with a 45% reduction in the annualized relapse rate over the study’s treatment period of 96 to 144 weeks, said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel and of the DECIDE study’s advisory committee. DAC HYP “has the potential to be a new once-monthly treatment option for patients with relapsing MS,” he said.

Treatment with DAC HYP was associated with an increased risk of infections, cutaneous adverse effects, and hepatic enzyme abnormalities, which were “manageable with standard monitoring and medical interventions,” Dr. Kappos said.

DAC HYP is a humanized monoclonal antibody that selectively blocks the high-affinity interleukin-2 receptor subunit CD25, which is expressed at high levels on T cells that are abnormally activated in MS. The biological effects of CD25 blockade include the inhibition of activated T cell responses and “normalization of lymphoid tissue inducer cell numbers,” he said.

Reduction in Relapse Rate Was Highly Significant
The DECIDE phase III study randomized 919 patients to treatment with 150 mg of DAC HYP administered subcutaneously once every four weeks and 922 patients to treatment with 30 mg of IFN β-1a administered intramuscularly once per week. Mean age of the patients was 36 years, 68% were women, and they had been diagnosed with MS for a mean of five years. Patients in both groups had had a similar mean number of relapses within the previous year (between 0.7 and 0.8); 21% had highly active MS, and 41% had been on disease-modifying treatments previously. Their mean Expanded Disability Status Scale (EDSS) score was between 1.2 and 1.3. In both arms, approximately 30% of patients discontinued treatment. The percentage of patients that discontinued treatment because of adverse events was higher in the DAC HYP-treated group.

The annualized relapse rate—the study’s primary end point—was 0.393 among those on IFN β-1a, compared with 0.216 among those on DAC HYP, a 45% reduction that was highly statistically significant, Dr. Kappos said.

Secondary end points included the proportion of patients who remained relapse-free, which was higher among those on DAC HYP at various points during the study (eg, 73% vs 59% at week 96, and 67% vs 51% at week 144). The risk of relapse was reduced by 41%.

Other secondary end points were MRI-defined lesions at week 96. The number of new or newly enlarging T2 hyperintense lesions at that point was reduced by 54%, compared with IFN β-1a. There were similar reductions in new T1 black holes, which were reduced by 52%, and in gadolinium-enhancing lesions, which were reduced by 65%. There was a significant positive effect of treatment on brain volume over time, which was possible to detect because the study was so large, Dr. Kappos said.

At three months, the risk of progression was reduced by 16% among those on DAC HYP, compared with those on IFN β-1a, although the effect was not statistically significant. At six months, the risk was reduced by 27%. The proportion of patients on DAC HYP with a clinically meaningful worsening in patient-reported physical impact of MS (defined by at least a 7.5-point decrease on MSIS-29-PHYS) was reduced by 24%, compared with those on IFN β-1a. The reduction was not statistically significant.

Hepatic Abnormalities Were More Common in Daclizumab Patients
The incidence of any type of adverse event was 91% in both groups, and infections, cutaneous events, and hepatic abnormalities were more common among those treated with DAC HYP. Serious adverse events were higher among those on DAC HYP (24% vs 21%); when MS relapses were excluded, the rates were 15% and 10%. Treatment discontinuations due to an adverse event other than an MS relapse were 14% among those on DAC HYP, compared with 9% of those on IFN β-1a. There were five deaths, one in a patient on the study drug and four among those on the comparator.

The rate of infectious adverse events was higher among those on DAC HYP (65% vs 57%), as was the rate of serious infectious adverse events (4% vs 2%). Cutaneous events were more common among those on DAC HYP (37% vs 19%), as were serious cutaneous adverse events (2% vs less than 1%).

Hepatic abnormalities were more common among those on DAC HYP, but were reversible, Dr. Kappos said. The rate of aspartate aminotransferase/alanine aminotransferase (AST/ALT) greater than five times the upper limit of normal (ULN) was 6% among those on DAC HYP, compared with 3% among those on IFN β-1a. The rate of ALT greater than three times the ULN and total bilirubin more than twice the ULN was less than 1% in each group. There was one case in each group that met Hy’s law criteria, which are used to predict the potential of drugs to cause serious liver injury.

Biogen Idec and AbbVie Biotherapeutics funded the study.

—Elizabeth Mechcatie

WASHINGTON, DC—Treatment with daclizumab high-yield process (DAC HYP), a first-in-class immunomodulator administered subcutaneously once per month, was significantly more effective on various outcomes in relapsing-remitting multiple sclerosis (MS) than was interferon (IFN) β-1a therapy, according to results from the international DECIDE study presented at the 67th Annual Meeting of the American Academy of Neurology.

The efficacy of DAC HYP was consistently superior to that of once-weekly intramuscular IFN β-1a “across key clinical, radiographic, and patient-reported MS outcome measures,” with a 45% reduction in the annualized relapse rate over the study’s treatment period of 96 to 144 weeks, said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel and of the DECIDE study’s advisory committee. DAC HYP “has the potential to be a new once-monthly treatment option for patients with relapsing MS,” he said.

Treatment with DAC HYP was associated with an increased risk of infections, cutaneous adverse effects, and hepatic enzyme abnormalities, which were “manageable with standard monitoring and medical interventions,” Dr. Kappos said.

DAC HYP is a humanized monoclonal antibody that selectively blocks the high-affinity interleukin-2 receptor subunit CD25, which is expressed at high levels on T cells that are abnormally activated in MS. The biological effects of CD25 blockade include the inhibition of activated T cell responses and “normalization of lymphoid tissue inducer cell numbers,” he said.

Reduction in Relapse Rate Was Highly Significant
The DECIDE phase III study randomized 919 patients to treatment with 150 mg of DAC HYP administered subcutaneously once every four weeks and 922 patients to treatment with 30 mg of IFN β-1a administered intramuscularly once per week. Mean age of the patients was 36 years, 68% were women, and they had been diagnosed with MS for a mean of five years. Patients in both groups had had a similar mean number of relapses within the previous year (between 0.7 and 0.8); 21% had highly active MS, and 41% had been on disease-modifying treatments previously. Their mean Expanded Disability Status Scale (EDSS) score was between 1.2 and 1.3. In both arms, approximately 30% of patients discontinued treatment. The percentage of patients that discontinued treatment because of adverse events was higher in the DAC HYP-treated group.

The annualized relapse rate—the study’s primary end point—was 0.393 among those on IFN β-1a, compared with 0.216 among those on DAC HYP, a 45% reduction that was highly statistically significant, Dr. Kappos said.

Secondary end points included the proportion of patients who remained relapse-free, which was higher among those on DAC HYP at various points during the study (eg, 73% vs 59% at week 96, and 67% vs 51% at week 144). The risk of relapse was reduced by 41%.

Other secondary end points were MRI-defined lesions at week 96. The number of new or newly enlarging T2 hyperintense lesions at that point was reduced by 54%, compared with IFN β-1a. There were similar reductions in new T1 black holes, which were reduced by 52%, and in gadolinium-enhancing lesions, which were reduced by 65%. There was a significant positive effect of treatment on brain volume over time, which was possible to detect because the study was so large, Dr. Kappos said.

At three months, the risk of progression was reduced by 16% among those on DAC HYP, compared with those on IFN β-1a, although the effect was not statistically significant. At six months, the risk was reduced by 27%. The proportion of patients on DAC HYP with a clinically meaningful worsening in patient-reported physical impact of MS (defined by at least a 7.5-point decrease on MSIS-29-PHYS) was reduced by 24%, compared with those on IFN β-1a. The reduction was not statistically significant.

Hepatic Abnormalities Were More Common in Daclizumab Patients
The incidence of any type of adverse event was 91% in both groups, and infections, cutaneous events, and hepatic abnormalities were more common among those treated with DAC HYP. Serious adverse events were higher among those on DAC HYP (24% vs 21%); when MS relapses were excluded, the rates were 15% and 10%. Treatment discontinuations due to an adverse event other than an MS relapse were 14% among those on DAC HYP, compared with 9% of those on IFN β-1a. There were five deaths, one in a patient on the study drug and four among those on the comparator.

The rate of infectious adverse events was higher among those on DAC HYP (65% vs 57%), as was the rate of serious infectious adverse events (4% vs 2%). Cutaneous events were more common among those on DAC HYP (37% vs 19%), as were serious cutaneous adverse events (2% vs less than 1%).

Hepatic abnormalities were more common among those on DAC HYP, but were reversible, Dr. Kappos said. The rate of aspartate aminotransferase/alanine aminotransferase (AST/ALT) greater than five times the upper limit of normal (ULN) was 6% among those on DAC HYP, compared with 3% among those on IFN β-1a. The rate of ALT greater than three times the ULN and total bilirubin more than twice the ULN was less than 1% in each group. There was one case in each group that met Hy’s law criteria, which are used to predict the potential of drugs to cause serious liver injury.

Biogen Idec and AbbVie Biotherapeutics funded the study.

—Elizabeth Mechcatie

After a fall, more than a quarter of MS patients report delayed initial recovery of laying on the floor or ground for more than 10 minutes, and a smaller fraction reported a long lie of 1 hour or more, according to a secondary analysis of 700 patients ages 55 and older from the North America Committee on Multiple Sclerosis registry.

Researchers used participants’ self-reported information about their most recent fall to determine rates of delayed initial recovery and a long lie and found:

• Of the 322 patients with fall information, 27.6% reported delayed initial recovery and 4.7% reported a long lie. 

• Factors associated with delayed initial recovery include longer disease duration (odds ratio [OR], 1.03), fall leading to fracture (OR, 2.73), needing help to get up (OR, 3.94), depression (OR, 1.96), and leg weakness (OR, 2.14).

Citation: Bisson EJ, Peterson EW, Finlayson M. Delayed initial recovery and long lie following a fall among middle-aged and older adults with multiple sclerosis. Arch Phys Med Rehabil. 2015. pii: S0003-9993(15)00378-0. doi:10.1016/j.apmr.2015.04.012.

Commentary: MS is a chronic disease that impacts patients in many different ways. Concerns are typically focused on relapse rates and MRI changes. Disease burden may include limitation of ambulation, impaired balance or vision, and cognitive problems. All of these problems might result in increased risk of falling. Economic impact related to MS also includes factors related to falling. Increased risk of falls—and the subsequent fear of falling—might limit independence and reduce quality of life. The costs related to injury from falling, restricted daily activities from this fear of falling, and attendant anxiety are not only likely significant costs but chronic costs as well. This article points out that fall risk evaluation and fall prevention are unmet needs in the continuum of MS care. — Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY 

After a fall, more than a quarter of MS patients report delayed initial recovery of laying on the floor or ground for more than 10 minutes, and a smaller fraction reported a long lie of 1 hour or more, according to a secondary analysis of 700 patients ages 55 and older from the North America Committee on Multiple Sclerosis registry.

Researchers used participants’ self-reported information about their most recent fall to determine rates of delayed initial recovery and a long lie and found:

• Of the 322 patients with fall information, 27.6% reported delayed initial recovery and 4.7% reported a long lie. 

• Factors associated with delayed initial recovery include longer disease duration (odds ratio [OR], 1.03), fall leading to fracture (OR, 2.73), needing help to get up (OR, 3.94), depression (OR, 1.96), and leg weakness (OR, 2.14).

Citation: Bisson EJ, Peterson EW, Finlayson M. Delayed initial recovery and long lie following a fall among middle-aged and older adults with multiple sclerosis. Arch Phys Med Rehabil. 2015. pii: S0003-9993(15)00378-0. doi:10.1016/j.apmr.2015.04.012.

Commentary: MS is a chronic disease that impacts patients in many different ways. Concerns are typically focused on relapse rates and MRI changes. Disease burden may include limitation of ambulation, impaired balance or vision, and cognitive problems. All of these problems might result in increased risk of falling. Economic impact related to MS also includes factors related to falling. Increased risk of falls—and the subsequent fear of falling—might limit independence and reduce quality of life. The costs related to injury from falling, restricted daily activities from this fear of falling, and attendant anxiety are not only likely significant costs but chronic costs as well. This article points out that fall risk evaluation and fall prevention are unmet needs in the continuum of MS care. — Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY 

After a fall, more than a quarter of MS patients report delayed initial recovery of laying on the floor or ground for more than 10 minutes, and a smaller fraction reported a long lie of 1 hour or more, according to a secondary analysis of 700 patients ages 55 and older from the North America Committee on Multiple Sclerosis registry.

Researchers used participants’ self-reported information about their most recent fall to determine rates of delayed initial recovery and a long lie and found:

• Of the 322 patients with fall information, 27.6% reported delayed initial recovery and 4.7% reported a long lie. 

• Factors associated with delayed initial recovery include longer disease duration (odds ratio [OR], 1.03), fall leading to fracture (OR, 2.73), needing help to get up (OR, 3.94), depression (OR, 1.96), and leg weakness (OR, 2.14).

Citation: Bisson EJ, Peterson EW, Finlayson M. Delayed initial recovery and long lie following a fall among middle-aged and older adults with multiple sclerosis. Arch Phys Med Rehabil. 2015. pii: S0003-9993(15)00378-0. doi:10.1016/j.apmr.2015.04.012.

Commentary: MS is a chronic disease that impacts patients in many different ways. Concerns are typically focused on relapse rates and MRI changes. Disease burden may include limitation of ambulation, impaired balance or vision, and cognitive problems. All of these problems might result in increased risk of falling. Economic impact related to MS also includes factors related to falling. Increased risk of falls—and the subsequent fear of falling—might limit independence and reduce quality of life. The costs related to injury from falling, restricted daily activities from this fear of falling, and attendant anxiety are not only likely significant costs but chronic costs as well. This article points out that fall risk evaluation and fall prevention are unmet needs in the continuum of MS care. — Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY 

Over the past 50 years, excess mortality rates among patients with multiple sclerosis (MS) relative to the general population has not changed, with female patients at a greater disadvantage than males, according to a meta-analysis of 12 studies spanning from 1949 to 2012.

Investigators determined all-cause, cause-specific, and gender-specific crude mortality rates to assess standardized mortality ratios (SMRs) in 27,423 MS patients and found the following SMRs:

• Pooled all-cause: 2.8

• All-cause, male: 2.56

• All-cause, female: 3.06

• Cancer: 0.89

• Cardiovascular: 1.29

• Suicide: 2.13

• Respiratory disease and infection: 2.91

Citation: Manouchehrinia A, Tanasescu R, Tench CR, Constantinescu CS. Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios. J Neurol Neurosurg Psychiatry. 2015. doi:10.1136/jnnp-2015-310361.

Over the past 50 years, excess mortality rates among patients with multiple sclerosis (MS) relative to the general population has not changed, with female patients at a greater disadvantage than males, according to a meta-analysis of 12 studies spanning from 1949 to 2012.

Investigators determined all-cause, cause-specific, and gender-specific crude mortality rates to assess standardized mortality ratios (SMRs) in 27,423 MS patients and found the following SMRs:

• Pooled all-cause: 2.8

• All-cause, male: 2.56

• All-cause, female: 3.06

• Cancer: 0.89

• Cardiovascular: 1.29

• Suicide: 2.13

• Respiratory disease and infection: 2.91

Citation: Manouchehrinia A, Tanasescu R, Tench CR, Constantinescu CS. Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios. J Neurol Neurosurg Psychiatry. 2015. doi:10.1136/jnnp-2015-310361.

Over the past 50 years, excess mortality rates among patients with multiple sclerosis (MS) relative to the general population has not changed, with female patients at a greater disadvantage than males, according to a meta-analysis of 12 studies spanning from 1949 to 2012.

Investigators determined all-cause, cause-specific, and gender-specific crude mortality rates to assess standardized mortality ratios (SMRs) in 27,423 MS patients and found the following SMRs:

• Pooled all-cause: 2.8

• All-cause, male: 2.56

• All-cause, female: 3.06

• Cancer: 0.89

• Cardiovascular: 1.29

• Suicide: 2.13

• Respiratory disease and infection: 2.91

Citation: Manouchehrinia A, Tanasescu R, Tench CR, Constantinescu CS. Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios. J Neurol Neurosurg Psychiatry. 2015. doi:10.1136/jnnp-2015-310361.

Established risk factors for multiple sclerosis (MS) do not appear to impact risk of transverse myelitis (TM) or neuromyelitis optica (NMO), according to a case-control study of participants in the Accelerated Cure Project for Multiple Sclerosis.

Researchers analyzed 1,237 MS cases, 98 NMO cases, 133 TM cases, and 488 healthy controls for MS risk factors including smoking history, a history of infectious mononucleosis, anti-EBNA1 Ab titers, and HLA-DR15, and found:

• Risk factors and odds of MS were as expected.

• There was little evidence of an association between the risk factors for MS and increased odds of NMO or TM.

Citation: Simon KC, Schmidt H, Loud S, Ascherio A. Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis. Mult Scler. 2015;21(6):703-709. doi:10.1177/1352458514551780.

Established risk factors for multiple sclerosis (MS) do not appear to impact risk of transverse myelitis (TM) or neuromyelitis optica (NMO), according to a case-control study of participants in the Accelerated Cure Project for Multiple Sclerosis.

Researchers analyzed 1,237 MS cases, 98 NMO cases, 133 TM cases, and 488 healthy controls for MS risk factors including smoking history, a history of infectious mononucleosis, anti-EBNA1 Ab titers, and HLA-DR15, and found:

• Risk factors and odds of MS were as expected.

• There was little evidence of an association between the risk factors for MS and increased odds of NMO or TM.

Citation: Simon KC, Schmidt H, Loud S, Ascherio A. Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis. Mult Scler. 2015;21(6):703-709. doi:10.1177/1352458514551780.

Established risk factors for multiple sclerosis (MS) do not appear to impact risk of transverse myelitis (TM) or neuromyelitis optica (NMO), according to a case-control study of participants in the Accelerated Cure Project for Multiple Sclerosis.

Researchers analyzed 1,237 MS cases, 98 NMO cases, 133 TM cases, and 488 healthy controls for MS risk factors including smoking history, a history of infectious mononucleosis, anti-EBNA1 Ab titers, and HLA-DR15, and found:

• Risk factors and odds of MS were as expected.

• There was little evidence of an association between the risk factors for MS and increased odds of NMO or TM.

Citation: Simon KC, Schmidt H, Loud S, Ascherio A. Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis. Mult Scler. 2015;21(6):703-709. doi:10.1177/1352458514551780.

The stress of being a caregiver to a patient with multiple sclerosis can result in substantial physical and psychological health concerns, and have a negative impact on employment, according to a survey of 1,446 care partners from the North American Research Committee on Multiple Sclerosis (NARCOMS).

Researchers analyzed data from an online questionnaire, including demographic characteristics, health status, caregiver burden as measured by the Zarit Caregiver Burden Interview, and impact on employment. They found:

• The average Zarit score was 24.6, which is in the mild caregiver burden range.

• Female caregivers reported higher levels of burden and stress than their male counterparts, and were more likely to use medication for stress, anxiety, and mood disorders.

• Male caregivers had higher rates of physical complaints than females.

• Care partners of patients with primary progressive MS reported greater perceived burden than those with secondary progressive MS and relapsing-remitting MS.

• In the past year, more than 40% of care partners had missed work due to caregiving responsibilities.   

Citation: McKenzie T, Quig ME, Tyry T, et al. Care partners and multiple sclerosis: differential impact on men and women. Int J MS Care. 2015. doi:10.7224/1537-2073.2014-083 [epub ahead of print].

The stress of being a caregiver to a patient with multiple sclerosis can result in substantial physical and psychological health concerns, and have a negative impact on employment, according to a survey of 1,446 care partners from the North American Research Committee on Multiple Sclerosis (NARCOMS).

Researchers analyzed data from an online questionnaire, including demographic characteristics, health status, caregiver burden as measured by the Zarit Caregiver Burden Interview, and impact on employment. They found:

• The average Zarit score was 24.6, which is in the mild caregiver burden range.

• Female caregivers reported higher levels of burden and stress than their male counterparts, and were more likely to use medication for stress, anxiety, and mood disorders.

• Male caregivers had higher rates of physical complaints than females.

• Care partners of patients with primary progressive MS reported greater perceived burden than those with secondary progressive MS and relapsing-remitting MS.

• In the past year, more than 40% of care partners had missed work due to caregiving responsibilities.   

Citation: McKenzie T, Quig ME, Tyry T, et al. Care partners and multiple sclerosis: differential impact on men and women. Int J MS Care. 2015. doi:10.7224/1537-2073.2014-083 [epub ahead of print].

The stress of being a caregiver to a patient with multiple sclerosis can result in substantial physical and psychological health concerns, and have a negative impact on employment, according to a survey of 1,446 care partners from the North American Research Committee on Multiple Sclerosis (NARCOMS).

Researchers analyzed data from an online questionnaire, including demographic characteristics, health status, caregiver burden as measured by the Zarit Caregiver Burden Interview, and impact on employment. They found:

• The average Zarit score was 24.6, which is in the mild caregiver burden range.

• Female caregivers reported higher levels of burden and stress than their male counterparts, and were more likely to use medication for stress, anxiety, and mood disorders.

• Male caregivers had higher rates of physical complaints than females.

• Care partners of patients with primary progressive MS reported greater perceived burden than those with secondary progressive MS and relapsing-remitting MS.

• In the past year, more than 40% of care partners had missed work due to caregiving responsibilities.   

Citation: McKenzie T, Quig ME, Tyry T, et al. Care partners and multiple sclerosis: differential impact on men and women. Int J MS Care. 2015. doi:10.7224/1537-2073.2014-083 [epub ahead of print].

A purported multiple sclerosis cure widely known as the “liberation” procedure — venoplasty to treat chronic cerebrospinal venous insufficiency — has patients traveling abroad against doctor advice to receive the unregulated procedure.

An analysis of data from the Canadian Survey of Health Lifestyle and Aging with MS, which included 753 patients over the age of 55 years old with 20 years or more of MS symptoms, found 13% underwent the alternative treatment. Researchers determined the following odds ratio for 5 factors:

• Living alone, 0.24

• Diagnosis of anxiety, 0.29

• Rating of neurologist’s helpfulness, 0.56

• Body mass index, 0.93

• Perceived physical impact of MS, 1.02

The study authors recommend physicians provide information on the risks and benefits of unregulated procedures to patients and their families who are dissatisfied with their neurologists.

Citation: Ploughman M, Manning OJ, Beaulieu S, et al.  Predictors of chronic cerebrospinal venous insufficiency procedure use among older people with multiple sclerosis: a national case-control study. BMC Health Serv Res. 2015. 15:161. doi:10.1186/s12913-015-835-y.

A purported multiple sclerosis cure widely known as the “liberation” procedure — venoplasty to treat chronic cerebrospinal venous insufficiency — has patients traveling abroad against doctor advice to receive the unregulated procedure.

An analysis of data from the Canadian Survey of Health Lifestyle and Aging with MS, which included 753 patients over the age of 55 years old with 20 years or more of MS symptoms, found 13% underwent the alternative treatment. Researchers determined the following odds ratio for 5 factors:

• Living alone, 0.24

• Diagnosis of anxiety, 0.29

• Rating of neurologist’s helpfulness, 0.56

• Body mass index, 0.93

• Perceived physical impact of MS, 1.02

The study authors recommend physicians provide information on the risks and benefits of unregulated procedures to patients and their families who are dissatisfied with their neurologists.

Citation: Ploughman M, Manning OJ, Beaulieu S, et al.  Predictors of chronic cerebrospinal venous insufficiency procedure use among older people with multiple sclerosis: a national case-control study. BMC Health Serv Res. 2015. 15:161. doi:10.1186/s12913-015-835-y.

A purported multiple sclerosis cure widely known as the “liberation” procedure — venoplasty to treat chronic cerebrospinal venous insufficiency — has patients traveling abroad against doctor advice to receive the unregulated procedure.

An analysis of data from the Canadian Survey of Health Lifestyle and Aging with MS, which included 753 patients over the age of 55 years old with 20 years or more of MS symptoms, found 13% underwent the alternative treatment. Researchers determined the following odds ratio for 5 factors:

• Living alone, 0.24

• Diagnosis of anxiety, 0.29

• Rating of neurologist’s helpfulness, 0.56

• Body mass index, 0.93

• Perceived physical impact of MS, 1.02

The study authors recommend physicians provide information on the risks and benefits of unregulated procedures to patients and their families who are dissatisfied with their neurologists.

Citation: Ploughman M, Manning OJ, Beaulieu S, et al.  Predictors of chronic cerebrospinal venous insufficiency procedure use among older people with multiple sclerosis: a national case-control study. BMC Health Serv Res. 2015. 15:161. doi:10.1186/s12913-015-835-y.