Multiple Sclerosis Hub

LYON, FRANCE—In blood samples drawn a median of nine years prior to multiple sclerosis (MS) onset, intermediate levels of retinol binding protein (RBP), a surrogate marker for vitamin A, were associated with a 55% decrease in MS risk compared with lower levels, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“Vitamin A is needed for suppression of proinflammatory pathways, which may explain the association,” said Jonatan Salzer, MD, a doctoral student at Umeå University in Sverige, Sweden, and colleagues.

The investigators also conducted a post hoc analysis of younger participants and found that signs of inflammation, assessed using C-reactive protein (CRP) as a marker, were associated with a 61% decreased risk of MS.

Vitamin A and MS risk
To examine the link between vitamin A and MS, the researchers performed a nested case-control study of prospectively collected blood samples from 192 persons with MS and 37 pregnant mothers whose children had later developed MS. The 291,500 samples were identified in two biobanks in northern Sweden. From these biobanks, matched controls were also selected.

Measurements of RBP and CRP were performed with enzyme-linked immunosorbent assays (ELISAs), and the risk of MS was calculated with matched logistic regression. Because CRP levels could potentially distort the correlation between RBP and vitamin A, the study authors adjusted for CRP levels in multivariable analyses.
   

Results showed that RBP levels within the second quintile were associated with a lower risk of MS (odds ratio, 0.45) than those within the first quintile. The odds ratios of MS then increased toward 1.0 for quintiles three to five, describing a U-shaped pattern of MS risk over RBP quintiles. This suggests that both insufficient and excessive levels of RBP might be risk factors for MS.

In addition, an analysis of samples from pregnant mothers showed that gestational RBP and CRP levels had no effect on MS risk in the offspring. Adjustment for CRP levels did not change these results, noted the researchers.

Support for the Hygiene Hypothesis
Dr. Salzer and his coauthors focused on CRP levels in a post hoc analysis of young subjects, defined as those younger than the median age of 26.4 at sampling. In this analysis, CRP levels of 10 mg/L or greater were associated with a 61% decreased risk of MS (odds ratio, 0.39).

“This association between elevated CRP levels in young persons and a lower risk of MS supports the importance of the hygiene hypothesis in MS etiopathogenesis,” said Dr. Salzer. He added that previous epidemiologic research suggests that MS risk is largely established in young adulthood and that childhood infections might be linked to a decreased MS risk.

Dr. Salzer emphasized the need for other researchers to replicate his group’s findings. “If [the results are] replicated, further studies are needed that look into environment–environment and gene–environment interactions,” he told Neurology Reviews. “For example, high vitamin A levels may antagonize the beneficial effects of vitamin D, as they compete over the same nuclear receptor. This [factor] might explain why high RBP levels are associated with a higher MS risk, compared to intermediate [levels] in our material. Presumably, vitamin A may be of interest in all future studies investigating vitamin D and MS. We hope that the study will be an inspiration for future research, and that such research might help us understand the complex line of events that subsequently lead to MS.”                               

LYON, FRANCE—In blood samples drawn a median of nine years prior to multiple sclerosis (MS) onset, intermediate levels of retinol binding protein (RBP), a surrogate marker for vitamin A, were associated with a 55% decrease in MS risk compared with lower levels, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“Vitamin A is needed for suppression of proinflammatory pathways, which may explain the association,” said Jonatan Salzer, MD, a doctoral student at Umeå University in Sverige, Sweden, and colleagues.

The investigators also conducted a post hoc analysis of younger participants and found that signs of inflammation, assessed using C-reactive protein (CRP) as a marker, were associated with a 61% decreased risk of MS.

Vitamin A and MS risk
To examine the link between vitamin A and MS, the researchers performed a nested case-control study of prospectively collected blood samples from 192 persons with MS and 37 pregnant mothers whose children had later developed MS. The 291,500 samples were identified in two biobanks in northern Sweden. From these biobanks, matched controls were also selected.

Measurements of RBP and CRP were performed with enzyme-linked immunosorbent assays (ELISAs), and the risk of MS was calculated with matched logistic regression. Because CRP levels could potentially distort the correlation between RBP and vitamin A, the study authors adjusted for CRP levels in multivariable analyses.
   

Results showed that RBP levels within the second quintile were associated with a lower risk of MS (odds ratio, 0.45) than those within the first quintile. The odds ratios of MS then increased toward 1.0 for quintiles three to five, describing a U-shaped pattern of MS risk over RBP quintiles. This suggests that both insufficient and excessive levels of RBP might be risk factors for MS.

In addition, an analysis of samples from pregnant mothers showed that gestational RBP and CRP levels had no effect on MS risk in the offspring. Adjustment for CRP levels did not change these results, noted the researchers.

Support for the Hygiene Hypothesis
Dr. Salzer and his coauthors focused on CRP levels in a post hoc analysis of young subjects, defined as those younger than the median age of 26.4 at sampling. In this analysis, CRP levels of 10 mg/L or greater were associated with a 61% decreased risk of MS (odds ratio, 0.39).

“This association between elevated CRP levels in young persons and a lower risk of MS supports the importance of the hygiene hypothesis in MS etiopathogenesis,” said Dr. Salzer. He added that previous epidemiologic research suggests that MS risk is largely established in young adulthood and that childhood infections might be linked to a decreased MS risk.

Dr. Salzer emphasized the need for other researchers to replicate his group’s findings. “If [the results are] replicated, further studies are needed that look into environment–environment and gene–environment interactions,” he told Neurology Reviews. “For example, high vitamin A levels may antagonize the beneficial effects of vitamin D, as they compete over the same nuclear receptor. This [factor] might explain why high RBP levels are associated with a higher MS risk, compared to intermediate [levels] in our material. Presumably, vitamin A may be of interest in all future studies investigating vitamin D and MS. We hope that the study will be an inspiration for future research, and that such research might help us understand the complex line of events that subsequently lead to MS.”                               

LYON, FRANCE—In blood samples drawn a median of nine years prior to multiple sclerosis (MS) onset, intermediate levels of retinol binding protein (RBP), a surrogate marker for vitamin A, were associated with a 55% decrease in MS risk compared with lower levels, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“Vitamin A is needed for suppression of proinflammatory pathways, which may explain the association,” said Jonatan Salzer, MD, a doctoral student at Umeå University in Sverige, Sweden, and colleagues.

The investigators also conducted a post hoc analysis of younger participants and found that signs of inflammation, assessed using C-reactive protein (CRP) as a marker, were associated with a 61% decreased risk of MS.

Vitamin A and MS risk
To examine the link between vitamin A and MS, the researchers performed a nested case-control study of prospectively collected blood samples from 192 persons with MS and 37 pregnant mothers whose children had later developed MS. The 291,500 samples were identified in two biobanks in northern Sweden. From these biobanks, matched controls were also selected.

Measurements of RBP and CRP were performed with enzyme-linked immunosorbent assays (ELISAs), and the risk of MS was calculated with matched logistic regression. Because CRP levels could potentially distort the correlation between RBP and vitamin A, the study authors adjusted for CRP levels in multivariable analyses.
   

Results showed that RBP levels within the second quintile were associated with a lower risk of MS (odds ratio, 0.45) than those within the first quintile. The odds ratios of MS then increased toward 1.0 for quintiles three to five, describing a U-shaped pattern of MS risk over RBP quintiles. This suggests that both insufficient and excessive levels of RBP might be risk factors for MS.

In addition, an analysis of samples from pregnant mothers showed that gestational RBP and CRP levels had no effect on MS risk in the offspring. Adjustment for CRP levels did not change these results, noted the researchers.

Support for the Hygiene Hypothesis
Dr. Salzer and his coauthors focused on CRP levels in a post hoc analysis of young subjects, defined as those younger than the median age of 26.4 at sampling. In this analysis, CRP levels of 10 mg/L or greater were associated with a 61% decreased risk of MS (odds ratio, 0.39).

“This association between elevated CRP levels in young persons and a lower risk of MS supports the importance of the hygiene hypothesis in MS etiopathogenesis,” said Dr. Salzer. He added that previous epidemiologic research suggests that MS risk is largely established in young adulthood and that childhood infections might be linked to a decreased MS risk.

Dr. Salzer emphasized the need for other researchers to replicate his group’s findings. “If [the results are] replicated, further studies are needed that look into environment–environment and gene–environment interactions,” he told Neurology Reviews. “For example, high vitamin A levels may antagonize the beneficial effects of vitamin D, as they compete over the same nuclear receptor. This [factor] might explain why high RBP levels are associated with a higher MS risk, compared to intermediate [levels] in our material. Presumably, vitamin A may be of interest in all future studies investigating vitamin D and MS. We hope that the study will be an inspiration for future research, and that such research might help us understand the complex line of events that subsequently lead to MS.”                               

LYON, FRANCE—Patients with multiple sclerosis (MS) may have stronger preferences for drugs that prevent long-term disability progression or MRI changes than for drugs that prevent relapses, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Preventing relapses, however, is the most common outcome in clinical trials. Patients with MS also may prefer drugs that substantially improve how they feel, but this criterion is not an efficacy outcome of MS drugs.

Leslie S. Wilson, PhD, Professor of Clinical Pharmacy at the University of California, San Francisco, and colleagues found that a 30% risk of fatal side effects had a larger negative effect on patient preference than any other characteristic of a hypothetical drug. In addition, patients preferred once daily oral drug administration to all other routes and frequencies of injection.

Rating Hypothetical Drugs
To understand patient preferences for the risks and benefits of hypothetical disease-modifying therapies (DMTs), Dr. Wilson and her team administered a card-sort conjoint analysis survey and paper questionnaire to 50 adult patients with relapsing-remitting MS. The investigators created the cards using a fractional factorial design, and each card contained eight attributes, including “Improve Symptoms,” “Common Side Effects,” “Severe Side Effects,” “Administration,” and “Time on Market.” Each attribute was assigned one of four levels of risks and benefits. Patients rated 16 hypothetical DMTs and their current therapies by placing the corresponding cards on a number line that stretched from zero, which represented a “not acceptable” rating, to 10, which represented a “most favorable” rating.

Women accounted for 74% of the sample population, (mean age, 43). Approximately 74% of participants were Caucasian, 10% were Hispanic or Latino, and 16% were other ethnicities. A plurality of the patients (34%) took glatiramer acetate, 26% took interferons, 18% took no DMT, 12% took natalizumab, and 10% took another drug.

Risk of Fatal Side Effects Decreased Patient Preference Ratings
Patients rated a hypothetical drug 12% higher for each year that it prevented disability progression. All levels of subjective symptom improvement were preferred to no improvement. Patients also preferred hypothetical DMTs that prevented MRI changes for one additional year.

Every 1% increase in the risk of fatal side effects decreased patients’ preference ratings by 11%. Among nonfatal side effects, only mood or vision changes decreased patient preference. Preventing relapses and time on market were not associated with patient preference.

Results of this study were used to create a choice-based conjoint survey, standard gamble, and revised questionnaire for a larger study, said Dr. Wilson. The new study will “enable maximum acceptable risks to be calculated, further elucidating DMT preference and setting groundwork for improved patient-centered choices in the future,” she concluded.

—Erik Greb

LYON, FRANCE—Patients with multiple sclerosis (MS) may have stronger preferences for drugs that prevent long-term disability progression or MRI changes than for drugs that prevent relapses, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Preventing relapses, however, is the most common outcome in clinical trials. Patients with MS also may prefer drugs that substantially improve how they feel, but this criterion is not an efficacy outcome of MS drugs.

Leslie S. Wilson, PhD, Professor of Clinical Pharmacy at the University of California, San Francisco, and colleagues found that a 30% risk of fatal side effects had a larger negative effect on patient preference than any other characteristic of a hypothetical drug. In addition, patients preferred once daily oral drug administration to all other routes and frequencies of injection.

Rating Hypothetical Drugs
To understand patient preferences for the risks and benefits of hypothetical disease-modifying therapies (DMTs), Dr. Wilson and her team administered a card-sort conjoint analysis survey and paper questionnaire to 50 adult patients with relapsing-remitting MS. The investigators created the cards using a fractional factorial design, and each card contained eight attributes, including “Improve Symptoms,” “Common Side Effects,” “Severe Side Effects,” “Administration,” and “Time on Market.” Each attribute was assigned one of four levels of risks and benefits. Patients rated 16 hypothetical DMTs and their current therapies by placing the corresponding cards on a number line that stretched from zero, which represented a “not acceptable” rating, to 10, which represented a “most favorable” rating.

Women accounted for 74% of the sample population, (mean age, 43). Approximately 74% of participants were Caucasian, 10% were Hispanic or Latino, and 16% were other ethnicities. A plurality of the patients (34%) took glatiramer acetate, 26% took interferons, 18% took no DMT, 12% took natalizumab, and 10% took another drug.

Risk of Fatal Side Effects Decreased Patient Preference Ratings
Patients rated a hypothetical drug 12% higher for each year that it prevented disability progression. All levels of subjective symptom improvement were preferred to no improvement. Patients also preferred hypothetical DMTs that prevented MRI changes for one additional year.

Every 1% increase in the risk of fatal side effects decreased patients’ preference ratings by 11%. Among nonfatal side effects, only mood or vision changes decreased patient preference. Preventing relapses and time on market were not associated with patient preference.

Results of this study were used to create a choice-based conjoint survey, standard gamble, and revised questionnaire for a larger study, said Dr. Wilson. The new study will “enable maximum acceptable risks to be calculated, further elucidating DMT preference and setting groundwork for improved patient-centered choices in the future,” she concluded.

—Erik Greb

LYON, FRANCE—Patients with multiple sclerosis (MS) may have stronger preferences for drugs that prevent long-term disability progression or MRI changes than for drugs that prevent relapses, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Preventing relapses, however, is the most common outcome in clinical trials. Patients with MS also may prefer drugs that substantially improve how they feel, but this criterion is not an efficacy outcome of MS drugs.

Leslie S. Wilson, PhD, Professor of Clinical Pharmacy at the University of California, San Francisco, and colleagues found that a 30% risk of fatal side effects had a larger negative effect on patient preference than any other characteristic of a hypothetical drug. In addition, patients preferred once daily oral drug administration to all other routes and frequencies of injection.

Rating Hypothetical Drugs
To understand patient preferences for the risks and benefits of hypothetical disease-modifying therapies (DMTs), Dr. Wilson and her team administered a card-sort conjoint analysis survey and paper questionnaire to 50 adult patients with relapsing-remitting MS. The investigators created the cards using a fractional factorial design, and each card contained eight attributes, including “Improve Symptoms,” “Common Side Effects,” “Severe Side Effects,” “Administration,” and “Time on Market.” Each attribute was assigned one of four levels of risks and benefits. Patients rated 16 hypothetical DMTs and their current therapies by placing the corresponding cards on a number line that stretched from zero, which represented a “not acceptable” rating, to 10, which represented a “most favorable” rating.

Women accounted for 74% of the sample population, (mean age, 43). Approximately 74% of participants were Caucasian, 10% were Hispanic or Latino, and 16% were other ethnicities. A plurality of the patients (34%) took glatiramer acetate, 26% took interferons, 18% took no DMT, 12% took natalizumab, and 10% took another drug.

Risk of Fatal Side Effects Decreased Patient Preference Ratings
Patients rated a hypothetical drug 12% higher for each year that it prevented disability progression. All levels of subjective symptom improvement were preferred to no improvement. Patients also preferred hypothetical DMTs that prevented MRI changes for one additional year.

Every 1% increase in the risk of fatal side effects decreased patients’ preference ratings by 11%. Among nonfatal side effects, only mood or vision changes decreased patient preference. Preventing relapses and time on market were not associated with patient preference.

Results of this study were used to create a choice-based conjoint survey, standard gamble, and revised questionnaire for a larger study, said Dr. Wilson. The new study will “enable maximum acceptable risks to be calculated, further elucidating DMT preference and setting groundwork for improved patient-centered choices in the future,” she concluded.

—Erik Greb

In patients with relapsing-remitting multiple sclerosis (MS), assisted reproduction treatment (ART) was associated with a sevenfold increase in risk of new exacerbations and a ninefold increase in risk of MRI activity, according to research published online in the October 3 Annals of Neurology. In all, 73% of exacerbations were new, and 27% corresponded with worsening of pre-existing symptoms.

Jorge Correale, MD, Head of Neuroimmunology and Demyelinating Diseases at the Dr. Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues recruited 16 patients with relapsing-remitting MS for a prospective study of the effect of ART on disease activity. Eligible patients had tried to become pregnant naturally for 12 months without success. The researchers recruited 15 healthy volunteers and 15 patients with relapsing-remitting MS in remission as age- and gender-matched controls.

The 16 active patients received 26 cycles of hormonal treatment (ie, 100 to 450 IU/day of gonadotropin-releasing hormone and 150 to 225 IU/day of recombinant follicle-stimulating hormone for seven to 10 days). The researchers conducted neurologic exams, brain MRI, and immunology testing every three months for one year. The risk period was defined as three months following an ART cycle.

Twelve of the 16 active patients had exacerbations after receiving ART. The researchers observed relapses in 15 of the 26 cycles in the three-month period following ART. Annual exacerbation rate was 3.28 during the risk period, compared with 0.42 during the nonrisk period.

Imaging data were available for 94% of the active patients. On average, the 16 patients had 1.99 ± 0.3 new or enlarging T2 lesions and 1.27 ± 0.2 gadolinium-enhancing lesions during the risk period, compared with 0.36 ± 0.2 T2 lesions and 0.23 ± 0.1 gadolinium-enhancing lesions during the remaining observation period.

“ART involves complex and dynamic interactions between hormonal and immune factors, which could affect the course of an autoimmune disease, explaining increased disease activity,” said Dr. Correale. “Overall, these data demonstrate a significant increase of disease activity in MS patients after ART.… Neurologists should be aware of this risk and discuss pros and cons of the procedure with MS patients.”

In patients with relapsing-remitting multiple sclerosis (MS), assisted reproduction treatment (ART) was associated with a sevenfold increase in risk of new exacerbations and a ninefold increase in risk of MRI activity, according to research published online in the October 3 Annals of Neurology. In all, 73% of exacerbations were new, and 27% corresponded with worsening of pre-existing symptoms.

Jorge Correale, MD, Head of Neuroimmunology and Demyelinating Diseases at the Dr. Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues recruited 16 patients with relapsing-remitting MS for a prospective study of the effect of ART on disease activity. Eligible patients had tried to become pregnant naturally for 12 months without success. The researchers recruited 15 healthy volunteers and 15 patients with relapsing-remitting MS in remission as age- and gender-matched controls.

The 16 active patients received 26 cycles of hormonal treatment (ie, 100 to 450 IU/day of gonadotropin-releasing hormone and 150 to 225 IU/day of recombinant follicle-stimulating hormone for seven to 10 days). The researchers conducted neurologic exams, brain MRI, and immunology testing every three months for one year. The risk period was defined as three months following an ART cycle.

Twelve of the 16 active patients had exacerbations after receiving ART. The researchers observed relapses in 15 of the 26 cycles in the three-month period following ART. Annual exacerbation rate was 3.28 during the risk period, compared with 0.42 during the nonrisk period.

Imaging data were available for 94% of the active patients. On average, the 16 patients had 1.99 ± 0.3 new or enlarging T2 lesions and 1.27 ± 0.2 gadolinium-enhancing lesions during the risk period, compared with 0.36 ± 0.2 T2 lesions and 0.23 ± 0.1 gadolinium-enhancing lesions during the remaining observation period.

“ART involves complex and dynamic interactions between hormonal and immune factors, which could affect the course of an autoimmune disease, explaining increased disease activity,” said Dr. Correale. “Overall, these data demonstrate a significant increase of disease activity in MS patients after ART.… Neurologists should be aware of this risk and discuss pros and cons of the procedure with MS patients.”

In patients with relapsing-remitting multiple sclerosis (MS), assisted reproduction treatment (ART) was associated with a sevenfold increase in risk of new exacerbations and a ninefold increase in risk of MRI activity, according to research published online in the October 3 Annals of Neurology. In all, 73% of exacerbations were new, and 27% corresponded with worsening of pre-existing symptoms.

Jorge Correale, MD, Head of Neuroimmunology and Demyelinating Diseases at the Dr. Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues recruited 16 patients with relapsing-remitting MS for a prospective study of the effect of ART on disease activity. Eligible patients had tried to become pregnant naturally for 12 months without success. The researchers recruited 15 healthy volunteers and 15 patients with relapsing-remitting MS in remission as age- and gender-matched controls.

The 16 active patients received 26 cycles of hormonal treatment (ie, 100 to 450 IU/day of gonadotropin-releasing hormone and 150 to 225 IU/day of recombinant follicle-stimulating hormone for seven to 10 days). The researchers conducted neurologic exams, brain MRI, and immunology testing every three months for one year. The risk period was defined as three months following an ART cycle.

Twelve of the 16 active patients had exacerbations after receiving ART. The researchers observed relapses in 15 of the 26 cycles in the three-month period following ART. Annual exacerbation rate was 3.28 during the risk period, compared with 0.42 during the nonrisk period.

Imaging data were available for 94% of the active patients. On average, the 16 patients had 1.99 ± 0.3 new or enlarging T2 lesions and 1.27 ± 0.2 gadolinium-enhancing lesions during the risk period, compared with 0.36 ± 0.2 T2 lesions and 0.23 ± 0.1 gadolinium-enhancing lesions during the remaining observation period.

“ART involves complex and dynamic interactions between hormonal and immune factors, which could affect the course of an autoimmune disease, explaining increased disease activity,” said Dr. Correale. “Overall, these data demonstrate a significant increase of disease activity in MS patients after ART.… Neurologists should be aware of this risk and discuss pros and cons of the procedure with MS patients.”

SAN DIEGO—A drug’s safety profile and mode of administration are the most important considerations for physicians and patients evaluating disease-modifying therapies for multiple sclerosis (MS). However, for neurologists, drug efficacy is more important than the risk of adverse events, while the opposite is true for patients, according to a study presented at the Fourth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

Reduction in annual relapse rate was the third most important criterion for physicians choosing an MS therapy. The likelihood of flu-like symptoms and the risk of herpes virus infection, however, were more important for patients than the reduction in annual relapse rate. The amount of time that a drug had been on the market was the least important attribute for physicians and patients.

Evaluating MS Therapy Preferences
Aaron Miller, MD, Professor of Neurology at the Mount Sinai School of Medicine in New York City, and colleagues surveyed 504 patients and 100 neurologists to determine the relative influence that efficacy and tolerability attributes have on their selection of MS therapies. Participants were randomly assigned to one of two Internet-based stated-choice questionnaires that the researchers had developed to evaluate participants’ preferences.

The investigators performed univariate analysis to evaluate survey variables and analyzed stated-choice data with mixed logistic regression models, with the respondent as a random effect.

Dr. Miller’s group determined the relative importance of various drug attributes for the choice of medication, as well as the maximum acceptable risk.

Nearly 81% of patients were female, and the patients’ mean age was approximately 53. All patients had been diagnosed with MS. Approximately 78% of physicians were male, and 78% had been practicing for 11 years or more. A majority (51%) of physicians reported seeing between 15 and 30 patients with MS or clinically isolated syndrome per month.

Physicians Accept Greater Risk Than Patients
On average, patients were willing to accept a maximum risk of herpes virus infection of 1.9% for a 20% reduction in annual relapse rate. In contrast, physicians were willing to accept a 3.2% risk of herpes virus infection to achieve the same outcome. Patients were willing to accept a maximum risk of flu-like symptoms of 24.7% for a 20% reduction in annual relapse rate. Physicians were willing to accept a 100% risk of flu-like symptoms to achieve this outcome. The maximum acceptable risk of flu-like symptoms that physicians were willing to accept varied widely, however.

“The results of this study suggest a disconnect between MS patients and treating neurologists,” said Dr. Miller. “The variability in the attribute responses emphasizes the need for individualized discussions between health care providers and patients before deciding on any treatment choices,” he concluded.

SAN DIEGO—A drug’s safety profile and mode of administration are the most important considerations for physicians and patients evaluating disease-modifying therapies for multiple sclerosis (MS). However, for neurologists, drug efficacy is more important than the risk of adverse events, while the opposite is true for patients, according to a study presented at the Fourth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

Reduction in annual relapse rate was the third most important criterion for physicians choosing an MS therapy. The likelihood of flu-like symptoms and the risk of herpes virus infection, however, were more important for patients than the reduction in annual relapse rate. The amount of time that a drug had been on the market was the least important attribute for physicians and patients.

Evaluating MS Therapy Preferences
Aaron Miller, MD, Professor of Neurology at the Mount Sinai School of Medicine in New York City, and colleagues surveyed 504 patients and 100 neurologists to determine the relative influence that efficacy and tolerability attributes have on their selection of MS therapies. Participants were randomly assigned to one of two Internet-based stated-choice questionnaires that the researchers had developed to evaluate participants’ preferences.

The investigators performed univariate analysis to evaluate survey variables and analyzed stated-choice data with mixed logistic regression models, with the respondent as a random effect.

Dr. Miller’s group determined the relative importance of various drug attributes for the choice of medication, as well as the maximum acceptable risk.

Nearly 81% of patients were female, and the patients’ mean age was approximately 53. All patients had been diagnosed with MS. Approximately 78% of physicians were male, and 78% had been practicing for 11 years or more. A majority (51%) of physicians reported seeing between 15 and 30 patients with MS or clinically isolated syndrome per month.

Physicians Accept Greater Risk Than Patients
On average, patients were willing to accept a maximum risk of herpes virus infection of 1.9% for a 20% reduction in annual relapse rate. In contrast, physicians were willing to accept a 3.2% risk of herpes virus infection to achieve the same outcome. Patients were willing to accept a maximum risk of flu-like symptoms of 24.7% for a 20% reduction in annual relapse rate. Physicians were willing to accept a 100% risk of flu-like symptoms to achieve this outcome. The maximum acceptable risk of flu-like symptoms that physicians were willing to accept varied widely, however.

“The results of this study suggest a disconnect between MS patients and treating neurologists,” said Dr. Miller. “The variability in the attribute responses emphasizes the need for individualized discussions between health care providers and patients before deciding on any treatment choices,” he concluded.

SAN DIEGO—A drug’s safety profile and mode of administration are the most important considerations for physicians and patients evaluating disease-modifying therapies for multiple sclerosis (MS). However, for neurologists, drug efficacy is more important than the risk of adverse events, while the opposite is true for patients, according to a study presented at the Fourth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

Reduction in annual relapse rate was the third most important criterion for physicians choosing an MS therapy. The likelihood of flu-like symptoms and the risk of herpes virus infection, however, were more important for patients than the reduction in annual relapse rate. The amount of time that a drug had been on the market was the least important attribute for physicians and patients.

Evaluating MS Therapy Preferences
Aaron Miller, MD, Professor of Neurology at the Mount Sinai School of Medicine in New York City, and colleagues surveyed 504 patients and 100 neurologists to determine the relative influence that efficacy and tolerability attributes have on their selection of MS therapies. Participants were randomly assigned to one of two Internet-based stated-choice questionnaires that the researchers had developed to evaluate participants’ preferences.

The investigators performed univariate analysis to evaluate survey variables and analyzed stated-choice data with mixed logistic regression models, with the respondent as a random effect.

Dr. Miller’s group determined the relative importance of various drug attributes for the choice of medication, as well as the maximum acceptable risk.

Nearly 81% of patients were female, and the patients’ mean age was approximately 53. All patients had been diagnosed with MS. Approximately 78% of physicians were male, and 78% had been practicing for 11 years or more. A majority (51%) of physicians reported seeing between 15 and 30 patients with MS or clinically isolated syndrome per month.

Physicians Accept Greater Risk Than Patients
On average, patients were willing to accept a maximum risk of herpes virus infection of 1.9% for a 20% reduction in annual relapse rate. In contrast, physicians were willing to accept a 3.2% risk of herpes virus infection to achieve the same outcome. Patients were willing to accept a maximum risk of flu-like symptoms of 24.7% for a 20% reduction in annual relapse rate. Physicians were willing to accept a 100% risk of flu-like symptoms to achieve this outcome. The maximum acceptable risk of flu-like symptoms that physicians were willing to accept varied widely, however.

“The results of this study suggest a disconnect between MS patients and treating neurologists,” said Dr. Miller. “The variability in the attribute responses emphasizes the need for individualized discussions between health care providers and patients before deciding on any treatment choices,” he concluded.

LYON, FRANCE—The following news stories were originally written on site at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and posted on the Neurology Reviews website www.neurologyreviews.com. We have reproduced them here for readers who did not see our online conference reporting. More news from the ECTRIMS Congress can be found online and in upcoming issues of Neurology Reviews.

Postmarketing Safety Data Released for Ampyra (Dalfampridine)
Michele Jara, DSc, Director of Epidemiology at Accorda Therapeutics in Hawthorne, New Jersey, and colleagues presented the findings from a two-year safety study of Ampyra (dalfampridine) extended-release tablets (10 mg) indicated for the treatment of walking impairment in patients with multiple sclerosis (MS). Among the major findings, Dr. Jara reported that:

• The safety profile for Ampyra two years after FDA approval is similar to that observed in clinical trials.
• The most frequent associated adverse events were dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, back pain, and asthenia.
• Among the 62,400 patients prescribed Ampyra, the rate of seizure (4.6 per 1,000 patient-years of use) was comparable to that seen in the MS population overall. Length of treatment prior to seizure ranged from first dose to two years, with 20% of the seizures occurring within a week of starting treatment.

The analysis examined all postmarketing data that were reported to the drug maker (Acorda) and the FDA from March 2010 through March 2012.

Teva Announces Top-Line Data From the GALA Study—New Dosing Regimen for Glatiramer Acetate
Data from a phase III trial support the efficacy of a new dosing regimen for Copaxone (glatiramer acetate) for patients with relapsing-remitting multiple sclerosis (MS).

Teva Pharmaceutical Industries released data from the Glatiramer Acetate Low-Frequency Administration (GALA) study, which was designed to evaluate the efficacy, safety, and tolerability of 40 mg/mL of glatiramer acetate three times weekly instead of the 20-mg/mL daily subcutaneous injection that has been the recommended dose for almost two decades.

In the GALA study, a one-year, randomized, double-blind, placebo-controlled trial, glatiramer acetate 40 mg/mL injected three times weekly significantly reduced annualized relapse rates by 34.4% versus placebo. The cumulative number of new and enlarging T2 lesions was significantly reduced by the same percentage. In addition, a significant 44.8% reduction in the cumulative number of gadolinium-enhancing lesions was observed in patients treated with the investigational dosing regimen. At 12 months, there was no significant difference in percentage change of brain volume between the glatiramer acetate-treated patients and those receiving placebo. Discontinuation rates among the two cohorts were comparable.

Glatiramer acetate in a dose of 40 mg/mL also showed a favorable safety and tolerability profile. The overall frequency of adverse events in the GALA study was comparable to that of the placebo group. The most common reported adverse events were injection-site reactions, headaches, and nasopharyngitis.

The drug maker released only top-line data at a press conference. Lead study author Omar A. Khan, MD, Professor and Interim Chair of the Department of Neurology and Director of the Multiple Sclerosis Clinical Research Center and Image Analysis Laboratory at Wayne State University School of Medicine in Detroit, reported more detailed study results two days later on October 13 in a late-breaking news session of the 28th Congress of the ECTRIMS.

Second Phase III Study of Teriflunomide Confirms Significant Impact on Disability
Once-daily oral teriflunomide 14 mg significantly reduced the annualized relapse rate and slowed progression of disability in patients with relapsing forms of multiple sclerosis (MS) compared with placebo, according to data presented at the 28th Congress of ECTRIMS. In addition, the proportion of patients treated with teriflunomide who were relapse-free was significantly higher compared with placebo. 

Ludwig Kappos, MD, Chair of Neurology, University Hospital Basel, Switzerland, and colleagues presented the results of TOWER (Teriflunomide Oral in people With relapsing multiplE scleRosis), the second phase III randomized, double-blind trial of teriflunomide. “The TOWER study results are consistent with the phase III TEMSO data, both in terms of the effect on progression of disability and the manageable safety profile of teriflunomide,”

said Dr. Kappos.

TOWER enrolled 1,169 patients with relapsing-remitting MS across 26 countries and compared 7 mg or 14 mg once-daily oral teriflunomide with placebo.

Dr. Kappos reported that patients treated with 14 mg had a 36.3% reduction in annualized relapse rate (ARR) compared with placebo and 31.5% reduced risk of 12-week sustained disability progression, as measured by the Expanded Disability Status Scale, compared with placebo. Patients treated with 7 mg had a 22.3% reduction in ARR; there was no significant effect of 7 mg on disability progression.

Patients who completed the trial were followed for between 48 and 173 weeks. The average duration of teriflunomide exposure in TOWER was 18 months.

Adverse events observed in the trial were consistent with those seen in previous studies of teriflunomide in MS.

The proportion of patients with treatment-emergent adverse events was similar across all treatment arms. The most common adverse events reported more frequently in the treatment arms were headache, ALT (alanine aminotransferase) elevations, hair thinning, diarrhea, nausea, and neutropenia. As previously reported, there was one death from a respiratory infection in the placebo arm and three deaths in the teriflunomide arms. The three deaths in the treatment arms were attributed to a motor vehicle accident, a suicide, and sepsis.

Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key enzyme in de novo pyrimidine synthesis required for proliferation of rapidly dividing lymphocytes. Teriflunomide thus limits expansion of stimulated T- and B-cells thought responsible for the damaging inflammatory process associated with MS while preserving resting lymphocytes’ function for immune surveillance. Teriflunomide is marketed by Genzyme under the brand name Aubagio. The drug was approved by the FDA on September 12, 2012 as a once-daily, oral immunomodulator indicated for patients with relapsing forms of MS.

Long-Term Safety and Efficacy Data Released for Oral Fingolimod
Four-year data from the phase III FREEDOMS extension study highlight the sustained efficacy of oral fingolimod and reinforce the known safety profile.

At the 28th Congress of ECTRIMS, Ludwig Kappos, MD, and his colleagues presented postmarketing data on the efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (MS) receiving continuous or placebo-fingolimod switched therapy for as many as four years.

Dr. Kappos and colleagues reported that after switching from placebo to fingolimod in the FREEDOMS study extension, patients showed improvements in clinical and MRI outcomes, consistent with the effects observed in fingolimod-treated patients in the core study.

In addition, patients receiving continuous fingolimod treatment during the FREEDOMS core study and extension phase demonstrated sustained, low-disease activity on clinical and MRI end points in the extension phase. These patients also had better overall outcomes than patients switched from placebo to fingolimod.

In continuously treated patients, Dr. Kappos reported, the brain-volume loss benefits observed in the phase III FREEDOMS study were sustained during the extension phase, indicating a long-term effect of fingolimod for as many as four years. In patients switched from placebo to fingolimod, brain-loss benefits were observed early during the first year of active treatment.

Brain-volume loss outcomes were better in continuously treated patients than in switch patients, indicating a smaller overall loss in brain volume with earlier initiation of fingolimod treatment. The percentage of patients free of three-month confirmed disability progression at the end of the study was 74.2% in the continuous 1.25-mg dosage group, 73.9% in the continuous 0.5-mg dosage group, and 66.3% in the placebo-fingolimod switched group.

The percentage of patients free of six-month confirmed disability progression at the end of the study was 79.3% in the continuous 1.25-mg dosage group, 80% in the continuous 0.5-mg dosage group, and 72.7% in the placebo-fingolimod switched group.

Annualized relapse rates at the end of the study were 0.164 in the continuous 1.25-mg dosage group, 0.185 in the continuous 0.5-mg dosage group, and 0.357 in the placebo-fingolimod switched group.

Mean percentage of brain-volume change at the end of the study was -1.6 in the continuous 1.25-mg dosage group, -1.7 in the continuous 0.5-mg dosage group, and -2.2 in the placebo-fingolimod switched group.

LYON, FRANCE—The following news stories were originally written on site at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and posted on the Neurology Reviews website www.neurologyreviews.com. We have reproduced them here for readers who did not see our online conference reporting. More news from the ECTRIMS Congress can be found online and in upcoming issues of Neurology Reviews.

Postmarketing Safety Data Released for Ampyra (Dalfampridine)
Michele Jara, DSc, Director of Epidemiology at Accorda Therapeutics in Hawthorne, New Jersey, and colleagues presented the findings from a two-year safety study of Ampyra (dalfampridine) extended-release tablets (10 mg) indicated for the treatment of walking impairment in patients with multiple sclerosis (MS). Among the major findings, Dr. Jara reported that:

• The safety profile for Ampyra two years after FDA approval is similar to that observed in clinical trials.
• The most frequent associated adverse events were dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, back pain, and asthenia.
• Among the 62,400 patients prescribed Ampyra, the rate of seizure (4.6 per 1,000 patient-years of use) was comparable to that seen in the MS population overall. Length of treatment prior to seizure ranged from first dose to two years, with 20% of the seizures occurring within a week of starting treatment.

The analysis examined all postmarketing data that were reported to the drug maker (Acorda) and the FDA from March 2010 through March 2012.

Teva Announces Top-Line Data From the GALA Study—New Dosing Regimen for Glatiramer Acetate
Data from a phase III trial support the efficacy of a new dosing regimen for Copaxone (glatiramer acetate) for patients with relapsing-remitting multiple sclerosis (MS).

Teva Pharmaceutical Industries released data from the Glatiramer Acetate Low-Frequency Administration (GALA) study, which was designed to evaluate the efficacy, safety, and tolerability of 40 mg/mL of glatiramer acetate three times weekly instead of the 20-mg/mL daily subcutaneous injection that has been the recommended dose for almost two decades.

In the GALA study, a one-year, randomized, double-blind, placebo-controlled trial, glatiramer acetate 40 mg/mL injected three times weekly significantly reduced annualized relapse rates by 34.4% versus placebo. The cumulative number of new and enlarging T2 lesions was significantly reduced by the same percentage. In addition, a significant 44.8% reduction in the cumulative number of gadolinium-enhancing lesions was observed in patients treated with the investigational dosing regimen. At 12 months, there was no significant difference in percentage change of brain volume between the glatiramer acetate-treated patients and those receiving placebo. Discontinuation rates among the two cohorts were comparable.

Glatiramer acetate in a dose of 40 mg/mL also showed a favorable safety and tolerability profile. The overall frequency of adverse events in the GALA study was comparable to that of the placebo group. The most common reported adverse events were injection-site reactions, headaches, and nasopharyngitis.

The drug maker released only top-line data at a press conference. Lead study author Omar A. Khan, MD, Professor and Interim Chair of the Department of Neurology and Director of the Multiple Sclerosis Clinical Research Center and Image Analysis Laboratory at Wayne State University School of Medicine in Detroit, reported more detailed study results two days later on October 13 in a late-breaking news session of the 28th Congress of the ECTRIMS.

Second Phase III Study of Teriflunomide Confirms Significant Impact on Disability
Once-daily oral teriflunomide 14 mg significantly reduced the annualized relapse rate and slowed progression of disability in patients with relapsing forms of multiple sclerosis (MS) compared with placebo, according to data presented at the 28th Congress of ECTRIMS. In addition, the proportion of patients treated with teriflunomide who were relapse-free was significantly higher compared with placebo. 

Ludwig Kappos, MD, Chair of Neurology, University Hospital Basel, Switzerland, and colleagues presented the results of TOWER (Teriflunomide Oral in people With relapsing multiplE scleRosis), the second phase III randomized, double-blind trial of teriflunomide. “The TOWER study results are consistent with the phase III TEMSO data, both in terms of the effect on progression of disability and the manageable safety profile of teriflunomide,”

said Dr. Kappos.

TOWER enrolled 1,169 patients with relapsing-remitting MS across 26 countries and compared 7 mg or 14 mg once-daily oral teriflunomide with placebo.

Dr. Kappos reported that patients treated with 14 mg had a 36.3% reduction in annualized relapse rate (ARR) compared with placebo and 31.5% reduced risk of 12-week sustained disability progression, as measured by the Expanded Disability Status Scale, compared with placebo. Patients treated with 7 mg had a 22.3% reduction in ARR; there was no significant effect of 7 mg on disability progression.

Patients who completed the trial were followed for between 48 and 173 weeks. The average duration of teriflunomide exposure in TOWER was 18 months.

Adverse events observed in the trial were consistent with those seen in previous studies of teriflunomide in MS.

The proportion of patients with treatment-emergent adverse events was similar across all treatment arms. The most common adverse events reported more frequently in the treatment arms were headache, ALT (alanine aminotransferase) elevations, hair thinning, diarrhea, nausea, and neutropenia. As previously reported, there was one death from a respiratory infection in the placebo arm and three deaths in the teriflunomide arms. The three deaths in the treatment arms were attributed to a motor vehicle accident, a suicide, and sepsis.

Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key enzyme in de novo pyrimidine synthesis required for proliferation of rapidly dividing lymphocytes. Teriflunomide thus limits expansion of stimulated T- and B-cells thought responsible for the damaging inflammatory process associated with MS while preserving resting lymphocytes’ function for immune surveillance. Teriflunomide is marketed by Genzyme under the brand name Aubagio. The drug was approved by the FDA on September 12, 2012 as a once-daily, oral immunomodulator indicated for patients with relapsing forms of MS.

Long-Term Safety and Efficacy Data Released for Oral Fingolimod
Four-year data from the phase III FREEDOMS extension study highlight the sustained efficacy of oral fingolimod and reinforce the known safety profile.

At the 28th Congress of ECTRIMS, Ludwig Kappos, MD, and his colleagues presented postmarketing data on the efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (MS) receiving continuous or placebo-fingolimod switched therapy for as many as four years.

Dr. Kappos and colleagues reported that after switching from placebo to fingolimod in the FREEDOMS study extension, patients showed improvements in clinical and MRI outcomes, consistent with the effects observed in fingolimod-treated patients in the core study.

In addition, patients receiving continuous fingolimod treatment during the FREEDOMS core study and extension phase demonstrated sustained, low-disease activity on clinical and MRI end points in the extension phase. These patients also had better overall outcomes than patients switched from placebo to fingolimod.

In continuously treated patients, Dr. Kappos reported, the brain-volume loss benefits observed in the phase III FREEDOMS study were sustained during the extension phase, indicating a long-term effect of fingolimod for as many as four years. In patients switched from placebo to fingolimod, brain-loss benefits were observed early during the first year of active treatment.

Brain-volume loss outcomes were better in continuously treated patients than in switch patients, indicating a smaller overall loss in brain volume with earlier initiation of fingolimod treatment. The percentage of patients free of three-month confirmed disability progression at the end of the study was 74.2% in the continuous 1.25-mg dosage group, 73.9% in the continuous 0.5-mg dosage group, and 66.3% in the placebo-fingolimod switched group.

The percentage of patients free of six-month confirmed disability progression at the end of the study was 79.3% in the continuous 1.25-mg dosage group, 80% in the continuous 0.5-mg dosage group, and 72.7% in the placebo-fingolimod switched group.

Annualized relapse rates at the end of the study were 0.164 in the continuous 1.25-mg dosage group, 0.185 in the continuous 0.5-mg dosage group, and 0.357 in the placebo-fingolimod switched group.

Mean percentage of brain-volume change at the end of the study was -1.6 in the continuous 1.25-mg dosage group, -1.7 in the continuous 0.5-mg dosage group, and -2.2 in the placebo-fingolimod switched group.

LYON, FRANCE—The following news stories were originally written on site at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and posted on the Neurology Reviews website www.neurologyreviews.com. We have reproduced them here for readers who did not see our online conference reporting. More news from the ECTRIMS Congress can be found online and in upcoming issues of Neurology Reviews.

Postmarketing Safety Data Released for Ampyra (Dalfampridine)
Michele Jara, DSc, Director of Epidemiology at Accorda Therapeutics in Hawthorne, New Jersey, and colleagues presented the findings from a two-year safety study of Ampyra (dalfampridine) extended-release tablets (10 mg) indicated for the treatment of walking impairment in patients with multiple sclerosis (MS). Among the major findings, Dr. Jara reported that:

• The safety profile for Ampyra two years after FDA approval is similar to that observed in clinical trials.
• The most frequent associated adverse events were dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, back pain, and asthenia.
• Among the 62,400 patients prescribed Ampyra, the rate of seizure (4.6 per 1,000 patient-years of use) was comparable to that seen in the MS population overall. Length of treatment prior to seizure ranged from first dose to two years, with 20% of the seizures occurring within a week of starting treatment.

The analysis examined all postmarketing data that were reported to the drug maker (Acorda) and the FDA from March 2010 through March 2012.

Teva Announces Top-Line Data From the GALA Study—New Dosing Regimen for Glatiramer Acetate
Data from a phase III trial support the efficacy of a new dosing regimen for Copaxone (glatiramer acetate) for patients with relapsing-remitting multiple sclerosis (MS).

Teva Pharmaceutical Industries released data from the Glatiramer Acetate Low-Frequency Administration (GALA) study, which was designed to evaluate the efficacy, safety, and tolerability of 40 mg/mL of glatiramer acetate three times weekly instead of the 20-mg/mL daily subcutaneous injection that has been the recommended dose for almost two decades.

In the GALA study, a one-year, randomized, double-blind, placebo-controlled trial, glatiramer acetate 40 mg/mL injected three times weekly significantly reduced annualized relapse rates by 34.4% versus placebo. The cumulative number of new and enlarging T2 lesions was significantly reduced by the same percentage. In addition, a significant 44.8% reduction in the cumulative number of gadolinium-enhancing lesions was observed in patients treated with the investigational dosing regimen. At 12 months, there was no significant difference in percentage change of brain volume between the glatiramer acetate-treated patients and those receiving placebo. Discontinuation rates among the two cohorts were comparable.

Glatiramer acetate in a dose of 40 mg/mL also showed a favorable safety and tolerability profile. The overall frequency of adverse events in the GALA study was comparable to that of the placebo group. The most common reported adverse events were injection-site reactions, headaches, and nasopharyngitis.

The drug maker released only top-line data at a press conference. Lead study author Omar A. Khan, MD, Professor and Interim Chair of the Department of Neurology and Director of the Multiple Sclerosis Clinical Research Center and Image Analysis Laboratory at Wayne State University School of Medicine in Detroit, reported more detailed study results two days later on October 13 in a late-breaking news session of the 28th Congress of the ECTRIMS.

Second Phase III Study of Teriflunomide Confirms Significant Impact on Disability
Once-daily oral teriflunomide 14 mg significantly reduced the annualized relapse rate and slowed progression of disability in patients with relapsing forms of multiple sclerosis (MS) compared with placebo, according to data presented at the 28th Congress of ECTRIMS. In addition, the proportion of patients treated with teriflunomide who were relapse-free was significantly higher compared with placebo. 

Ludwig Kappos, MD, Chair of Neurology, University Hospital Basel, Switzerland, and colleagues presented the results of TOWER (Teriflunomide Oral in people With relapsing multiplE scleRosis), the second phase III randomized, double-blind trial of teriflunomide. “The TOWER study results are consistent with the phase III TEMSO data, both in terms of the effect on progression of disability and the manageable safety profile of teriflunomide,”

said Dr. Kappos.

TOWER enrolled 1,169 patients with relapsing-remitting MS across 26 countries and compared 7 mg or 14 mg once-daily oral teriflunomide with placebo.

Dr. Kappos reported that patients treated with 14 mg had a 36.3% reduction in annualized relapse rate (ARR) compared with placebo and 31.5% reduced risk of 12-week sustained disability progression, as measured by the Expanded Disability Status Scale, compared with placebo. Patients treated with 7 mg had a 22.3% reduction in ARR; there was no significant effect of 7 mg on disability progression.

Patients who completed the trial were followed for between 48 and 173 weeks. The average duration of teriflunomide exposure in TOWER was 18 months.

Adverse events observed in the trial were consistent with those seen in previous studies of teriflunomide in MS.

The proportion of patients with treatment-emergent adverse events was similar across all treatment arms. The most common adverse events reported more frequently in the treatment arms were headache, ALT (alanine aminotransferase) elevations, hair thinning, diarrhea, nausea, and neutropenia. As previously reported, there was one death from a respiratory infection in the placebo arm and three deaths in the teriflunomide arms. The three deaths in the treatment arms were attributed to a motor vehicle accident, a suicide, and sepsis.

Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key enzyme in de novo pyrimidine synthesis required for proliferation of rapidly dividing lymphocytes. Teriflunomide thus limits expansion of stimulated T- and B-cells thought responsible for the damaging inflammatory process associated with MS while preserving resting lymphocytes’ function for immune surveillance. Teriflunomide is marketed by Genzyme under the brand name Aubagio. The drug was approved by the FDA on September 12, 2012 as a once-daily, oral immunomodulator indicated for patients with relapsing forms of MS.

Long-Term Safety and Efficacy Data Released for Oral Fingolimod
Four-year data from the phase III FREEDOMS extension study highlight the sustained efficacy of oral fingolimod and reinforce the known safety profile.

At the 28th Congress of ECTRIMS, Ludwig Kappos, MD, and his colleagues presented postmarketing data on the efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (MS) receiving continuous or placebo-fingolimod switched therapy for as many as four years.

Dr. Kappos and colleagues reported that after switching from placebo to fingolimod in the FREEDOMS study extension, patients showed improvements in clinical and MRI outcomes, consistent with the effects observed in fingolimod-treated patients in the core study.

In addition, patients receiving continuous fingolimod treatment during the FREEDOMS core study and extension phase demonstrated sustained, low-disease activity on clinical and MRI end points in the extension phase. These patients also had better overall outcomes than patients switched from placebo to fingolimod.

In continuously treated patients, Dr. Kappos reported, the brain-volume loss benefits observed in the phase III FREEDOMS study were sustained during the extension phase, indicating a long-term effect of fingolimod for as many as four years. In patients switched from placebo to fingolimod, brain-loss benefits were observed early during the first year of active treatment.

Brain-volume loss outcomes were better in continuously treated patients than in switch patients, indicating a smaller overall loss in brain volume with earlier initiation of fingolimod treatment. The percentage of patients free of three-month confirmed disability progression at the end of the study was 74.2% in the continuous 1.25-mg dosage group, 73.9% in the continuous 0.5-mg dosage group, and 66.3% in the placebo-fingolimod switched group.

The percentage of patients free of six-month confirmed disability progression at the end of the study was 79.3% in the continuous 1.25-mg dosage group, 80% in the continuous 0.5-mg dosage group, and 72.7% in the placebo-fingolimod switched group.

Annualized relapse rates at the end of the study were 0.164 in the continuous 1.25-mg dosage group, 0.185 in the continuous 0.5-mg dosage group, and 0.357 in the placebo-fingolimod switched group.

Mean percentage of brain-volume change at the end of the study was -1.6 in the continuous 1.25-mg dosage group, -1.7 in the continuous 0.5-mg dosage group, and -2.2 in the placebo-fingolimod switched group.

BG-12 (dimethyl fumarate) significantly reduced the annualized relapse rate among patients with multiple sclerosis (MS) compared with placebo, according to two studies published in the September 20 New England Journal of Medicine.

In one study, Robert J. Fox, MD, a staff neurologist and Medical Director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, and colleagues enrolled 1,417 patients in a multicenter, double-blind phase III trial of BG-12. Approximately equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 three times daily, 20 mg of glatiramer acetate, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

After two years, twice-daily BG-12 reduced the annualized relapse rate to 0.22. BG-12 thrice daily reduced the annualized relapse rate to 0.20. Compared with placebo, the drug significantly reduced the numbers of new or enlarging T2-weighted hyperintense lesions and new T1-weighted hypointense lesions.

In the second study, Ralf Gold, MD, Director of Neurology at St. Josef-Hospital in Bochum, Germany, and colleagues conducted a double-blind, phase III trial that included 952 patients with relapsing-remitting MS. Equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 thrice daily, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

Dr. Gold's group found that 27% of patients taking BG-12 twice daily had had a relapse at two years, compared with 26% of patients taking BG-12 thrice daily and 46% of patients taking placebo. The annualized relapse rate at two years was 0.17 for patients taking twice-daily BG-12 and 0.19 for patients taking thrice-daily BG-12. In contrast, control patients had a relapse rate of 0.36.

"The average age at onset of MS is in the late 20s, and it typically results in disability only after 15 to 20 years," said Allan H. Ropper, MD, Executive Vice Chair of Neurology at Brigham and Women's Hospital in Boston, in an accompanying editorial. "Even fumarate will need to prove that its efficacy is durable by reducing disability over the many decades that encompass the representative course of multiple sclerosis," he added.

BG-12 (dimethyl fumarate) significantly reduced the annualized relapse rate among patients with multiple sclerosis (MS) compared with placebo, according to two studies published in the September 20 New England Journal of Medicine.

In one study, Robert J. Fox, MD, a staff neurologist and Medical Director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, and colleagues enrolled 1,417 patients in a multicenter, double-blind phase III trial of BG-12. Approximately equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 three times daily, 20 mg of glatiramer acetate, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

After two years, twice-daily BG-12 reduced the annualized relapse rate to 0.22. BG-12 thrice daily reduced the annualized relapse rate to 0.20. Compared with placebo, the drug significantly reduced the numbers of new or enlarging T2-weighted hyperintense lesions and new T1-weighted hypointense lesions.

In the second study, Ralf Gold, MD, Director of Neurology at St. Josef-Hospital in Bochum, Germany, and colleagues conducted a double-blind, phase III trial that included 952 patients with relapsing-remitting MS. Equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 thrice daily, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

Dr. Gold's group found that 27% of patients taking BG-12 twice daily had had a relapse at two years, compared with 26% of patients taking BG-12 thrice daily and 46% of patients taking placebo. The annualized relapse rate at two years was 0.17 for patients taking twice-daily BG-12 and 0.19 for patients taking thrice-daily BG-12. In contrast, control patients had a relapse rate of 0.36.

"The average age at onset of MS is in the late 20s, and it typically results in disability only after 15 to 20 years," said Allan H. Ropper, MD, Executive Vice Chair of Neurology at Brigham and Women's Hospital in Boston, in an accompanying editorial. "Even fumarate will need to prove that its efficacy is durable by reducing disability over the many decades that encompass the representative course of multiple sclerosis," he added.

BG-12 (dimethyl fumarate) significantly reduced the annualized relapse rate among patients with multiple sclerosis (MS) compared with placebo, according to two studies published in the September 20 New England Journal of Medicine.

In one study, Robert J. Fox, MD, a staff neurologist and Medical Director at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, and colleagues enrolled 1,417 patients in a multicenter, double-blind phase III trial of BG-12. Approximately equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 three times daily, 20 mg of glatiramer acetate, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

After two years, twice-daily BG-12 reduced the annualized relapse rate to 0.22. BG-12 thrice daily reduced the annualized relapse rate to 0.20. Compared with placebo, the drug significantly reduced the numbers of new or enlarging T2-weighted hyperintense lesions and new T1-weighted hypointense lesions.

In the second study, Ralf Gold, MD, Director of Neurology at St. Josef-Hospital in Bochum, Germany, and colleagues conducted a double-blind, phase III trial that included 952 patients with relapsing-remitting MS. Equal groups of patients were randomized to 240 mg of BG-12 twice daily, 240 mg of BG-12 thrice daily, or placebo. The researchers performed standardized neurologic assessments every 12 weeks.

Dr. Gold's group found that 27% of patients taking BG-12 twice daily had had a relapse at two years, compared with 26% of patients taking BG-12 thrice daily and 46% of patients taking placebo. The annualized relapse rate at two years was 0.17 for patients taking twice-daily BG-12 and 0.19 for patients taking thrice-daily BG-12. In contrast, control patients had a relapse rate of 0.36.

"The average age at onset of MS is in the late 20s, and it typically results in disability only after 15 to 20 years," said Allan H. Ropper, MD, Executive Vice Chair of Neurology at Brigham and Women's Hospital in Boston, in an accompanying editorial. "Even fumarate will need to prove that its efficacy is durable by reducing disability over the many decades that encompass the representative course of multiple sclerosis," he added.

To read an accompanying article, please click here.

To read an accompanying article, please click here.

To read an accompanying article, please click here.

To read an accompanying article, please click here.

To read an accompanying article, please click here.

To read an accompanying article, please click here.