Multiple Sclerosis Hub

ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.

Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.

“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.

Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.

Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.

Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.

Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.

Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.

Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.

Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.

Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.

Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.

Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.

Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.

—Bruce Jancin
IMNG Medical News

ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.

Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.

“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.

Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.

Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.

Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.

Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.

Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.

Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.

Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.

Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.

Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.

Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.

Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.

—Bruce Jancin
IMNG Medical News

ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.

Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.

“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.

Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.

Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.

Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.

Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.

Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.

Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.

Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.

Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.

Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.

Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.

Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.

—Bruce Jancin
IMNG Medical News

SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.

Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.

Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).

At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.

Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.

Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.

The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.

The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.

—Erik Greb
Senior Associate Editor

Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.

Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.

Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.

SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.

Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.

Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).

At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.

Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.

Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.

The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.

The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.

—Erik Greb
Senior Associate Editor

Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.

Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.

Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.

SAN DIEGO—Simvastatin may reduce the rate of brain atrophy by approximately 40% in patients with secondary progressive multiple sclerosis (SPMS), according to data presented at the 65th Annual Meeting of the American Academy of Neurology. The effect may be apparent after one year of treatment. Simvastatin also may affect physician- and patient-reported outcomes for these individuals.

Patients Did Not Take MS Drugs
In the MS-STAT trial, Jeremy Chataway, PhD, Consultant Neurologist at the Queen Square MS Centre, National Hospital for Neurology and Neurosurgery in London, and colleagues randomized 140 patients with SPMS in a one-to-one ratio. Patients underwent an MRI at baseline and initially received 40 mg per day of simvastatin or placebo. After one month, the dose was increased to 80 mg, and the treatment continued for two years. One month after the end of treatment, patients underwent a second MRI. The baseline and final MRIs were taken while the patients were off medication to avoid possible pseudoatrophy effects of simvastatin, said Dr. Chataway. The study’s primary outcome was the annualized rate of brain atrophy.

Participants responded to the MS Impact Scale-29 (MSIS-29) at baseline and at 24 months. At the same times, the researchers administered the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).

At baseline, subjects with SPMS had been actively progressing for at least two years, could walk as far as 500 meters (EDSS 4.0) or at least 20 meters with bilateral assistance (6.5), and had a mean EDSS score of 5.8 and a median EDSS score of 6.0. No patients were taking disease-modifying treatments. Average disease duration was 20 years, and patients had had secondary progression for about seven years. Patients’ mean age was about 50.

Simvastatin Lessened the Impact of MS
More than 90% of patients returned for their second MRI, and a majority of patients were compliant with the medication. The mean rate of change in brain volume was about 0.6% per year among controls, compared with 0.3% per year among patients taking simvastatin.

Approximately 55% of patients taking placebo had higher EDSS scores after two years, compared with 40% of patients in the statin arm. At two years, patients taking simvastatin had lower MSIS-29 scores than patients taking placebo. Simvastatin did not affect MSFC scores, however.

The drug was associated with a 30% reduction in the accumulation of T2 lesions, but the difference was not statistically significant. The researchers found no difference in adverse events or serious adverse events between the two treatment arms.

The statin appeared not to affect any of the T-cell outcomes that the investigators measured. The lack of an effect suggests that simvastatin may work through a vascular, microvascular, or permeability mechanism, concluded Dr. Chataway.

—Erik Greb
Senior Associate Editor

Suggested Reading
Sorensen PS, Lycke J, Erälinna JP, et al. Simvastatin as add-on therapy to interferon b-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691-701.

Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608.

Zamvil SS, Steinman, L. Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS.

SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.

The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.

“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.

In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.

Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.

—M. Alexander Otto
IMNG Medical News

SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.

The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.

“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.

In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.

Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.

—M. Alexander Otto
IMNG Medical News

SAN DIEGO—Fingolimod slows brain atrophy in patients with multiple sclerosis (MS) and is the only approved drug that does so within the first six months of treatment, reported Jeffrey Cohen, MD, at the 65th Annual Meeting of the American Academy of Neurology.

The findings come from a combined analysis of the drug’s three clinical trials—FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which compared 0.5 mg and 1.25 mg daily against placebo for two years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which compared those doses against weekly intramuscular interferon beta-1a for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation using normalization of atrophy) at baseline and at six, 12, and 24 months. More than 3,000 patients ages 18 to 55 with clinically active relapsing-remitting MS participated.

“There was a consistent” 31% to 36% reduction in the rate of brain volume loss with both doses of fingolimod “compared to placebo and interferon beta-1a,” said Dr. Cohen. “There was no clear-cut dose effect between the two” doses. Dr. Cohen is Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic.

In the two trials with placebo arms, patients who had received fingolimod had volume losses of about 0.85%, compared with 1.31% in patients who had received placebo. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The “benefit was seen as early as six months, in both FREEDOMS and FREEDOMS II,” said Dr. Cohen. “In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss—in other words, no pseudoatrophy.”

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab and glatiramer acetate, he noted.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who received it, regardless of baseline characteristics, according to Dr. Cohen.

Weak correlations were observed between accumulations of T2 lesions and disability during the study, perhaps because “brain volume and measures of disability don’t change much over two years,” Dr. Cohen said.

—M. Alexander Otto
IMNG Medical News

ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.

Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.

According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”

Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.

—Glenn S. Williams
VP/Group Editor

Suggested Reading

Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.

Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.

Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.

ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.

Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.

According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”

Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.

—Glenn S. Williams
VP/Group Editor

Suggested Reading

Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.

Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.

Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.

ORLANDO—In anti-JCV antibody–positive natalizumab-treated patients with multiple sclerosis (MS) and no prior immunosuppressant (IS) use, a higher anti-JCV antibody index correlates with an increased risk of progressive multifocal leukoencephalopathy (PML), according to research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Tatiana Plavina, PhD, Meena Subramanyam, PhD, and colleagues from Biogen Idec, Inc, examined the association between anti-JCV antibody index (anti-JCV antibody level as measured using the STRATIFY JCV DxSelect assay [Focus Diagnostics, Cypress, California]) and PML risk in anti-JCV–positive patients enrolled in natalizumab clinical studies and from postmarketing settings. Anti-JCV antibody index data were available from 71 natalizumab-treated PML patients at least six months prior to PML diagnosis and from 2,522 non-PML anti-JCV antibody–positive patients.

Low Index, Lower Risk
In cross-sectional analyses, anti-JCV antibody index was not associated with duration of natalizumab treatment (less than or equal to 24 versus more than 24 infusions) or prior IS use but was significantly associated with PML risk. A different relationship was observed between anti-JCV antibody index and PML by prior IS use. Hence, the association between anti-JCV antibody index and PML risk was assessed using all available longitudinal data in anti-JCV–positive patients without prior IS use, and estimated odds ratios across a range of thresholds of interest varied from 7 to 23 for the occurrence of PML at higher versus lower index.

According to previous work by Bloomgren et al, risk of PML in natalizumab-treated anti-JCV antibody–negative patients with MS is less than or equal to 0.1/1000. Anti-JCV antibody–positive patients with no prior IS use who have low anti-JCV antibody index may have severalfold lower PML risk, compared with current risk estimates assigned to all anti-JCV antibody–positive patients with no prior IS use as per the current algorithm. The researchers concluded that “anti-JCV antibody index may further differentiate PML risk for natalizumab-treated anti-JCV antibody–positive MS patients with no prior IS use.”

Stability of the Index Over Time
The researchers also looked at the longitudinal stability of the anti-JCV antibody index. In the AFFIRM and STRATIFY-1 study cohorts, of those patients who tested anti-JCV antibody-negative at baseline, 87% remained consistently negative and 96% remained consistently at lower risk (anti-JCV antibody index less than or equal to 0.9, 1.2, or 1.5) for a period of 18 months, with testing every six months. “These analyses may potentially better inform PML risk in patients who seroconvert or test intermittently positive,” the researchers said. Further, the investigators noted that 96% of natalizumab-treated patients who developed PML and had two or more samples available (n = 25) had pre-PML samples with an index consistently above 0.9.

—Glenn S. Williams
VP/Group Editor

Suggested Reading

Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880.

Lee P Plavina T, Castro A, et al. A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.

Plavina T, Berman M, Njenga M, et al. Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma.

Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.

The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.

Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.

Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.

The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.

Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.

The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.

Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.

Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.

Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.

Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.

According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.

—Glenn S. Williams
Vice President, Group Editor

Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.

The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.

Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.

Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.

The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.

Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.

The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.

Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.

Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.

Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.

Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.

According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.

—Glenn S. Williams
Vice President, Group Editor

Disease-Modifying Therapies Affect Quality of Life Differently for Men and Women
After three years of disease-modifying therapy (DMT) for multiple sclerosis (MS), physical health-related quality of life (HRQL) declines were experienced by both men and women, but especially in men, according to a study presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Karen V. L. Turpin, MSc, BScN, a PhD student at the University of Alberta in Edmonton, Canada, and colleagues examined the course of changes in HRQL over a three-year period in men and women with relapsing-remitting MS who were being treated with DMTs. The researchers used data from a study of 185 patients with relapsing-remitting MS carried out in Saskatchewan, Canada, that was designed to evaluate the long-term impact of DMTs. Study participants completed the SF-36 HRQL survey at three time points: pre-DMT, follow-up at one year, and follow-up at three years. The researchers investigated the course of changes over time in SF-36 subscale scores and the summary scale scores stratified by sex.

The majority of the sample was female (70.3%). The average age of the sample at the study initiation was 39.2, and the average Expanded Disability Status Scale (EDSS) score was 2.4 (ambulatory with minimal to mild disability). For women, there were initial improvements in all scores at one year. At two years, all scores had decreased and three of the physical health subtest scores (but not the mental health scores) had fallen below initial values. Men showed improvement at one year on role limitations due to physical and mental health problems and on the mental health summary scale. Most men’s gains were retained through year three, but there were substantial declines in the physical HRQL domain scores that were greater than declines experienced by women.

Overall, the researchers found that, compared with pre-DMT scores, there were sustained improvements in mental health at three years, but declines in physical health. Sex differences were apparent in the patterns of improvement and worsening over the course of the three-year follow-up, with the degree of improvement and worsening being especially marked for men. The sustained improvement in mental health scores suggests that, despite a worsening physical health, DMTs may lead to better mental and social health. This is important, the researchers said, because psychosocial well-being has been reported to be the most salient aspect of health for persons with relapsing-remitting MS.

Exercise Training Reduces Fatigue in Patients With MS
Exercise training is associated with a significant moderate reduction in fatigue among patients with multiple sclerosis (MS), according to data presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Lara A. Pilutti, PhD, from the University of Illinois at Urbana-Champaign, and colleagues conducted a meta-analysis to provide a quantitative review of randomized controlled trials examining the effects of exercise training on symptomatic fatigue in persons with MS. Electronic databases (eg, Web of Science, PubMed, PsycINFO, and Google Scholar) were searched for articles published between 1960 and October 2012 using the key words fatigue, tiredness, energy, mood, or lassitude in combination with exercise, physical activity, rehabilitation, or fitness with the additional search term multiple sclerosis. The initial search resulted in 311 articles, of which 74 were reviewed in detail, and 17 met inclusion criteria and provided enough data to compute effect sizes.

The 43 effect sizes from 17 randomized controlled trials with 568 MS participants yielded a weighted mean effect size of 0.45. The weighted mean effect size was slightly heterogeneous. Exploratory moderator analyses indicated that study location, disease duration, training supervision, and mode of exercise might be important variables for understanding the effects of exercise training on symptomatic fatigue.

Overall, exercise training was associated with a significant, nearly one-half standard deviation reduction in symptomatic fatigue among persons with MS. The overall effect size was substantially higher than that reported in other meta-analyses examining the effect of exercise training on walking mobility and quality of life. Further, the researchers reported that the overall effect size found in this study represents a clinically significant change in fatigue with exercise training based on a one-point change in Fatigue Severity Scale scores.

The cumulative evidence supports the association of exercise training with a significant, moderate reduction in fatigue among persons with MS. Based on their findings, the researchers recommend that exercise training should be considered as an effective alternative therapy for the management of fatigue in persons with MS.

Multipotent Adult Progenitor Cells May Become a Viable Treatment for MS
Treatment of patients with multiple sclerosis (MS) with human multipotent adult progenitor cells (MAPCs) may provide clinical benefit through modulation of immune status and promotion of remyelination, according to basic science research presented at the Fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Stem cell therapies are currently being investigated as potential therapeutic treatments for autoimmune disorders such as MS. However, the mechanistic interaction between the diseased tissue environment and transplanted cells is often poorly understood, leading to inefficient or inappropriate applications of cell therapies that may not afford significant health benefits.

Jason A. Hamilton, PhD, from Athersys, Inc, and colleagues investigated the potential use of human MAPCs as a cellular therapeutic for the treatment of MS. Their research evaluated the cells’ efficacy, dose, window of therapeutic benefit, and effects upon remyelination.

Experimental allergic encephalomyelitis (EAE) was induced in C57Bl/6 mice. Efficacy was examined after administering 1, 3, or 9 million cells IV, compared to control animals administered vehicle. Cells or vehicle was administered after significant symptom onset, and behavior was monitored for 28 days by a blinded observer. Window of therapeutic benefit was examined by administering 1 million cells IV at different time points in the course of disease. Myelin content was examined via luxol fast blue (LFB) staining and electron microscopy (EM). Investigation of the direct effects of MAPC upon remyelination was achieved via direct injection of cells or vehicle into lysolecithin (LPC) lesions in adult rat spinal cords. Lesions were characterized via LFB staining and immunocytochemistry.

Significant and sustained behavioral improvement was observed in response to all cell doses tested, when administered after symptom onset. Presymptomatic treatment did not prevent disease onset. Examination of myelination status demonstrated decreased average area of demyelinated lesions in spinal cords of cell-treated animals, as well as a significant decrease in the number of complete lesions. Further analysis via EM showed abundant evidence of newly remyelinated axons within cell-treated animals. Subsequent studies in LPC-lesioned rat spinal cords demonstrated increased remyelination in cell-treated lesions associated with significant induction of M2 macrophages in the core of the lesion.

According to the researchers, the results of their studies suggest that treatment with MAPCs may provide clinical benefit to patients with MS.

—Glenn S. Williams
Vice President, Group Editor

SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.

At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.

The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.

Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.

Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.

By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).

—Erik Greb
Senior Associate Editor

Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].

SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.

At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.

The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.

Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.

Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.

By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).

—Erik Greb
Senior Associate Editor

Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].

SAN DIEGO—A new statistical model may be able to estimate a patient’s current risk of progressing from relapsing-remitting multiple sclerosis (MS) to secondary progressive MS. If future investigations prove the model robust, it eventually may help select high-risk patients for clinical trials and aid in the design of trials in which secondary progressive MS is an outcome, said Helen Tedeholm, MSci, a doctoral student at the University of Gothenburg in Sweden.

At the 65th Annual Meeting of the American Academy of Neurology, Ms. Tedeholm and colleagues presented their study of 157 untreated patients diagnosed with relapsing-remitting MS according to the Poser criteria. All patients had had a distinct second relapse of the disease and were followed up for more than 45 years.

The researchers created Poisson regression models with secondary progressive MS as an outcome using previously validated clinical characteristics as variables. The variables were confirmed for each patient as they arose at any time during the course of relapsing-remitting MS.

Of the original cohort, 118 patients developed secondary progressive MS. The risk of secondary progressive MS peaked when the patients were approximately age 30. Three of the variables that the investigators tested—current age, severity of the last relapse, and time since the last relapse—were independently significant predictors of transition to secondary progressive MS.

Ms. Tedeholm and colleagues developed a statistical model that included information from the second relapse onward, as well as the time and clinical characteristics of relapses. The risk of transition to secondary progressive MS increased sharply with a relapse with a high severity score, but it decreased with a relapse with a low severity score.

By applying the model to individual patients, the researchers calculated their current risk of developing secondary progressive MS. Among the study participants, 40 had the highest risk of progressive MS (greater than 0.14 events/year), and 41 had the lowest risk (less than 0.015 events/year).

—Erik Greb
Senior Associate Editor

Suggested Reading
Martinelli-Boneschi F, Esposito F, Brambilla P, et al. A genome-wide association study in progressive multiple sclerosis. Mult Scler. 2012;18(10):1384-1394. Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for development of secondary progressive multiple sclerosis: A study in IRAN, Guilan. J Neurol Sci. 2013 Apr 26 [Epub ahead of print].

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.