Multiple Sclerosis

Baseline MRI measures of lesion volume and brain atrophy predicted distinct long-term clinical changes in patients with early multiple sclerosis, reported authors of a small study published in Multiple Sclerosis and Related Disorders.

"We have identified several interesting putative biomarkers that are strongly associated with clinical worsening in early MS," wrote Dr. Amir-Hadi Maghzi of the University of California, San Francisco, and his associates.

The study included 43 patients with early MS, of whom 22 completed the 3-year assessment, the researchers said. MRI showed that T2 lesion volume significantly predicted longitudinal changes in the Paced Auditory Serial Addition Test (P = .004), they reported (Mult. Scler. Relat. Disord. 2014 July 23 [doi:10.1016/j.msard.2014.07.003]). The patients had participated in a randomized, double-blind, placebo-controlled trial at two centers that assessed the possible neuroprotective effects of riluzole in combination with intramuscular interferon beta-1a.

In addition, three baseline measures of atrophy – brain parenchymal volume and normal-appearing white and grey matter volumes – predicted longitudinal changes in the MS Functional Composite score and the Timed 25-Foot Walk (all P values less than .041), the researchers said. The different findings for lesion and brain volume could reflect distinct disease processes, the investigators added.

Dr. Maghzi and his colleagues calculated longitudinal changes in brain volume by using the SIENA (Structural Image Evaluation Using Normalization of Atrophy) analysis. They counted T2 and contrast-enhancing lesions by simultaneously visualizing T2 and T1 images before and after enhancement. Most MRI measures did not correlate with clinical outcomes at baseline, they noted.

In longitudinal analyses, every 1% decrease in brain volume was associated with a 1.14-point drop on the Symbol Digit Modalities Test (SDMT; P = .03). For MS patients, a 4- to 5-point decrease in SDMT is associated with job loss, according to the authors.

For every 1% decrease in brain volume, low-contrast letter acuity also declined by an average of nearly 1.5 letters, the investigators said.

The National MS Society and the Multiple Sclerosis International Federation funded the research. Three coauthors reported serving as committee members or receiving consulting fees, honoraria, or free study medication from Biogen Idec, Novartis, Mylan, Roche, Acorda, Bionure, CNS Imaging Consultant, Hoffman-LaRoche, Genzyme, Teva, Sanofi-Aventis, and Genentech.

Baseline MRI measures of lesion volume and brain atrophy predicted distinct long-term clinical changes in patients with early multiple sclerosis, reported authors of a small study published in Multiple Sclerosis and Related Disorders.

"We have identified several interesting putative biomarkers that are strongly associated with clinical worsening in early MS," wrote Dr. Amir-Hadi Maghzi of the University of California, San Francisco, and his associates.

The study included 43 patients with early MS, of whom 22 completed the 3-year assessment, the researchers said. MRI showed that T2 lesion volume significantly predicted longitudinal changes in the Paced Auditory Serial Addition Test (P = .004), they reported (Mult. Scler. Relat. Disord. 2014 July 23 [doi:10.1016/j.msard.2014.07.003]). The patients had participated in a randomized, double-blind, placebo-controlled trial at two centers that assessed the possible neuroprotective effects of riluzole in combination with intramuscular interferon beta-1a.

In addition, three baseline measures of atrophy – brain parenchymal volume and normal-appearing white and grey matter volumes – predicted longitudinal changes in the MS Functional Composite score and the Timed 25-Foot Walk (all P values less than .041), the researchers said. The different findings for lesion and brain volume could reflect distinct disease processes, the investigators added.

Dr. Maghzi and his colleagues calculated longitudinal changes in brain volume by using the SIENA (Structural Image Evaluation Using Normalization of Atrophy) analysis. They counted T2 and contrast-enhancing lesions by simultaneously visualizing T2 and T1 images before and after enhancement. Most MRI measures did not correlate with clinical outcomes at baseline, they noted.

In longitudinal analyses, every 1% decrease in brain volume was associated with a 1.14-point drop on the Symbol Digit Modalities Test (SDMT; P = .03). For MS patients, a 4- to 5-point decrease in SDMT is associated with job loss, according to the authors.

For every 1% decrease in brain volume, low-contrast letter acuity also declined by an average of nearly 1.5 letters, the investigators said.

The National MS Society and the Multiple Sclerosis International Federation funded the research. Three coauthors reported serving as committee members or receiving consulting fees, honoraria, or free study medication from Biogen Idec, Novartis, Mylan, Roche, Acorda, Bionure, CNS Imaging Consultant, Hoffman-LaRoche, Genzyme, Teva, Sanofi-Aventis, and Genentech.

Baseline MRI measures of lesion volume and brain atrophy predicted distinct long-term clinical changes in patients with early multiple sclerosis, reported authors of a small study published in Multiple Sclerosis and Related Disorders.

"We have identified several interesting putative biomarkers that are strongly associated with clinical worsening in early MS," wrote Dr. Amir-Hadi Maghzi of the University of California, San Francisco, and his associates.

The study included 43 patients with early MS, of whom 22 completed the 3-year assessment, the researchers said. MRI showed that T2 lesion volume significantly predicted longitudinal changes in the Paced Auditory Serial Addition Test (P = .004), they reported (Mult. Scler. Relat. Disord. 2014 July 23 [doi:10.1016/j.msard.2014.07.003]). The patients had participated in a randomized, double-blind, placebo-controlled trial at two centers that assessed the possible neuroprotective effects of riluzole in combination with intramuscular interferon beta-1a.

In addition, three baseline measures of atrophy – brain parenchymal volume and normal-appearing white and grey matter volumes – predicted longitudinal changes in the MS Functional Composite score and the Timed 25-Foot Walk (all P values less than .041), the researchers said. The different findings for lesion and brain volume could reflect distinct disease processes, the investigators added.

Dr. Maghzi and his colleagues calculated longitudinal changes in brain volume by using the SIENA (Structural Image Evaluation Using Normalization of Atrophy) analysis. They counted T2 and contrast-enhancing lesions by simultaneously visualizing T2 and T1 images before and after enhancement. Most MRI measures did not correlate with clinical outcomes at baseline, they noted.

In longitudinal analyses, every 1% decrease in brain volume was associated with a 1.14-point drop on the Symbol Digit Modalities Test (SDMT; P = .03). For MS patients, a 4- to 5-point decrease in SDMT is associated with job loss, according to the authors.

For every 1% decrease in brain volume, low-contrast letter acuity also declined by an average of nearly 1.5 letters, the investigators said.

The National MS Society and the Multiple Sclerosis International Federation funded the research. Three coauthors reported serving as committee members or receiving consulting fees, honoraria, or free study medication from Biogen Idec, Novartis, Mylan, Roche, Acorda, Bionure, CNS Imaging Consultant, Hoffman-LaRoche, Genzyme, Teva, Sanofi-Aventis, and Genentech.

DALLAS—Neurologists who treat patients with multiple sclerosis (MS) sometimes must consider whether it is safe to administer vaccines to these individuals. The current literature indicates that live and killed vaccines are safe for patients with MS, according to a review presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

In addition, current disease-modifying therapies (DMTs) generally do not appear to affect the efficacy of vaccines. Fingolimod is the one DMT that raises concerns, however. Before starting fingolimod in a patient with MS, neurologists routinely assess the patient for an immune response to varicella zoster virus (VZV). If the results are negative, most neurologists will vaccinate the patient before treating him or her with fingolimod, said Patricia K. Coyle, MD, Director of the MS Comprehensive Care Center at Stony Brook Neurosciences Institute in New York.

Vaccines, Infections, and Relapses
Several studies suggest an association between benign viral infections and an increased MS relapse rate. One theory is that the infection increases the relapse rate by activating the immune system. As many as one-third of relapses are associated with a prior infection, said Dr. Coyle. “Therefore, vaccines should be beneficial in MS if they prevent infection, so long as they’re relatively safe,” she added. But vaccinations should not be administered during or shortly after relapses.

A 2001 study published in the New England Journal of Medicine followed 643 patients with MS for a four-year period. The patients’ rate of relapses was 2.3% during periods when they received a vaccination, compared with a range of 2.8% to 4% during periods when patients were not being vaccinated. The authors concluded that vaccines are not associated with an increased risk of relapses.

After reviewing studies of vaccines in patients with MS, the MS Council for Clinical Practice Guidelines concluded in 2002 that the evidence supported strategies to minimize infections that can trigger relapses. The panel also concluded that the vaccines for influenza, hepatitis B, varicella, tetanus, and Bacillus Calmette–Guérin were safe for patients with MS. The council endorsed killed vaccines and recommended that neurologists wait for four to six weeks after the onset of a relapse before vaccinating a patient with MS. Physicians should be consulted, however, before administering a live vaccine to a patient receiving an immunosuppressive agent, the panel added.

Specific Vaccines and MS
Researchers also have examined the safety of specific vaccines in patients with MS. The seasonal influenza vaccine may be the best-studied vaccine in this population. The consensus is that the killed virus vaccine is safe, even for patients on a DMT, but that the live vaccine should be avoided.

Three vaccines have raised concerns for patients with MS. Several reports associated the hepatitis B vaccine with demyelinating episodes, but, after reviewing the evidence, the Institute of Medicine concluded that it was safe for patients with MS. Similarly, the literature contains reports of immune-mediated complications of the human papillomavirus (HPV) vaccine in patients with MS, but the vaccine is now accepted as safe in this population.

One case report has discouraged physicians from giving yellow fever vaccine to patients with MS. This vaccine was associated with increased clinical attacks and increased MRI lesion activity, although the report contained a small number of patients. The vaccine is contraindicated in patients who take immunosuppression or immunomodulatory therapies.

A large case–control study presented at the 66th Annual Meeting of the American Academy of Neurology included 780 patients with MS and 3,885 controls. The researchers found no association between an increased risk of demyelinating disease and the hepatitis B vaccine, the HPV vaccine, or any other vaccine. Younger individuals appeared to have an increased risk of CNS expression of disease during the first 30 days after vaccination, but the association was not linked to any specific vaccine. “The ultimate conclusion of this database study was that there was no need to change our current vaccine policy in MS,” said Dr. Coyle.

DMTs and Vaccinations
Researchers also have studied whether DMTs affect a patient’s response to vaccinations. Interferon betas are associated with normal humoral and cellular immune responses to the influenza vaccine. Investigators know of no negative effects of glatiramer acetate that relate to vaccines. Natalizumab is associated with normal humoral responses to the influenza, tetanus, and keyhole limpet hemocyanin vaccines. Researchers found an association between teriflunomide and normal immune responses to the influenza and rabies vaccines. No data about dimethyl fumarate’s effect on vaccine response exist, but the National MS Society does not recommend administering live vaccines to patients with MS who take this drug, said Dr. Coyle.

A pilot study indicated that alemtuzumab is associated with normal responses to the meningococcus, pneumococcus, and diphtheria–pertussis–tetanus vaccines in most individuals. The vaccine did not work, however, if patients were vaccinated within several months of their treatment cycle. “The recommendation for alemtuzumab is that you either vaccinate before you give the therapy, or you wait at least six months after the treatment cycle,” said Dr. Coyle. If a neurologist vaccinates the patient six months after the treatment cycle, he or she should measure the patient’s antibody levels about a month later to confirm that the vaccine is working, she added.

Of all DMTs, fingolimod appears to have the most influence on a patient’s response to vaccination. The drug decreases the humoral response to the influenza, tetanus, and pneumococcal vaccines. Before initiating fingolimod, a neurologist should screen the patient for VZV antibodies. If the results are negative or show a low titer of VZV antibodies, neurologists may vaccinate the patient before starting fingolimod. Initiation of therapy should be delayed a month after completion of the vaccination, said Dr. Coyle. Patients taking fingolimod should not receive a live vaccine, and post treatment vaccination should be delayed until two months after the drug is stopped, she added

—Erik Greb

DALLAS—Neurologists who treat patients with multiple sclerosis (MS) sometimes must consider whether it is safe to administer vaccines to these individuals. The current literature indicates that live and killed vaccines are safe for patients with MS, according to a review presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

In addition, current disease-modifying therapies (DMTs) generally do not appear to affect the efficacy of vaccines. Fingolimod is the one DMT that raises concerns, however. Before starting fingolimod in a patient with MS, neurologists routinely assess the patient for an immune response to varicella zoster virus (VZV). If the results are negative, most neurologists will vaccinate the patient before treating him or her with fingolimod, said Patricia K. Coyle, MD, Director of the MS Comprehensive Care Center at Stony Brook Neurosciences Institute in New York.

Vaccines, Infections, and Relapses
Several studies suggest an association between benign viral infections and an increased MS relapse rate. One theory is that the infection increases the relapse rate by activating the immune system. As many as one-third of relapses are associated with a prior infection, said Dr. Coyle. “Therefore, vaccines should be beneficial in MS if they prevent infection, so long as they’re relatively safe,” she added. But vaccinations should not be administered during or shortly after relapses.

A 2001 study published in the New England Journal of Medicine followed 643 patients with MS for a four-year period. The patients’ rate of relapses was 2.3% during periods when they received a vaccination, compared with a range of 2.8% to 4% during periods when patients were not being vaccinated. The authors concluded that vaccines are not associated with an increased risk of relapses.

After reviewing studies of vaccines in patients with MS, the MS Council for Clinical Practice Guidelines concluded in 2002 that the evidence supported strategies to minimize infections that can trigger relapses. The panel also concluded that the vaccines for influenza, hepatitis B, varicella, tetanus, and Bacillus Calmette–Guérin were safe for patients with MS. The council endorsed killed vaccines and recommended that neurologists wait for four to six weeks after the onset of a relapse before vaccinating a patient with MS. Physicians should be consulted, however, before administering a live vaccine to a patient receiving an immunosuppressive agent, the panel added.

Specific Vaccines and MS
Researchers also have examined the safety of specific vaccines in patients with MS. The seasonal influenza vaccine may be the best-studied vaccine in this population. The consensus is that the killed virus vaccine is safe, even for patients on a DMT, but that the live vaccine should be avoided.

Three vaccines have raised concerns for patients with MS. Several reports associated the hepatitis B vaccine with demyelinating episodes, but, after reviewing the evidence, the Institute of Medicine concluded that it was safe for patients with MS. Similarly, the literature contains reports of immune-mediated complications of the human papillomavirus (HPV) vaccine in patients with MS, but the vaccine is now accepted as safe in this population.

One case report has discouraged physicians from giving yellow fever vaccine to patients with MS. This vaccine was associated with increased clinical attacks and increased MRI lesion activity, although the report contained a small number of patients. The vaccine is contraindicated in patients who take immunosuppression or immunomodulatory therapies.

A large case–control study presented at the 66th Annual Meeting of the American Academy of Neurology included 780 patients with MS and 3,885 controls. The researchers found no association between an increased risk of demyelinating disease and the hepatitis B vaccine, the HPV vaccine, or any other vaccine. Younger individuals appeared to have an increased risk of CNS expression of disease during the first 30 days after vaccination, but the association was not linked to any specific vaccine. “The ultimate conclusion of this database study was that there was no need to change our current vaccine policy in MS,” said Dr. Coyle.

DMTs and Vaccinations
Researchers also have studied whether DMTs affect a patient’s response to vaccinations. Interferon betas are associated with normal humoral and cellular immune responses to the influenza vaccine. Investigators know of no negative effects of glatiramer acetate that relate to vaccines. Natalizumab is associated with normal humoral responses to the influenza, tetanus, and keyhole limpet hemocyanin vaccines. Researchers found an association between teriflunomide and normal immune responses to the influenza and rabies vaccines. No data about dimethyl fumarate’s effect on vaccine response exist, but the National MS Society does not recommend administering live vaccines to patients with MS who take this drug, said Dr. Coyle.

A pilot study indicated that alemtuzumab is associated with normal responses to the meningococcus, pneumococcus, and diphtheria–pertussis–tetanus vaccines in most individuals. The vaccine did not work, however, if patients were vaccinated within several months of their treatment cycle. “The recommendation for alemtuzumab is that you either vaccinate before you give the therapy, or you wait at least six months after the treatment cycle,” said Dr. Coyle. If a neurologist vaccinates the patient six months after the treatment cycle, he or she should measure the patient’s antibody levels about a month later to confirm that the vaccine is working, she added.

Of all DMTs, fingolimod appears to have the most influence on a patient’s response to vaccination. The drug decreases the humoral response to the influenza, tetanus, and pneumococcal vaccines. Before initiating fingolimod, a neurologist should screen the patient for VZV antibodies. If the results are negative or show a low titer of VZV antibodies, neurologists may vaccinate the patient before starting fingolimod. Initiation of therapy should be delayed a month after completion of the vaccination, said Dr. Coyle. Patients taking fingolimod should not receive a live vaccine, and post treatment vaccination should be delayed until two months after the drug is stopped, she added

—Erik Greb

DALLAS—Neurologists who treat patients with multiple sclerosis (MS) sometimes must consider whether it is safe to administer vaccines to these individuals. The current literature indicates that live and killed vaccines are safe for patients with MS, according to a review presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

In addition, current disease-modifying therapies (DMTs) generally do not appear to affect the efficacy of vaccines. Fingolimod is the one DMT that raises concerns, however. Before starting fingolimod in a patient with MS, neurologists routinely assess the patient for an immune response to varicella zoster virus (VZV). If the results are negative, most neurologists will vaccinate the patient before treating him or her with fingolimod, said Patricia K. Coyle, MD, Director of the MS Comprehensive Care Center at Stony Brook Neurosciences Institute in New York.

Vaccines, Infections, and Relapses
Several studies suggest an association between benign viral infections and an increased MS relapse rate. One theory is that the infection increases the relapse rate by activating the immune system. As many as one-third of relapses are associated with a prior infection, said Dr. Coyle. “Therefore, vaccines should be beneficial in MS if they prevent infection, so long as they’re relatively safe,” she added. But vaccinations should not be administered during or shortly after relapses.

A 2001 study published in the New England Journal of Medicine followed 643 patients with MS for a four-year period. The patients’ rate of relapses was 2.3% during periods when they received a vaccination, compared with a range of 2.8% to 4% during periods when patients were not being vaccinated. The authors concluded that vaccines are not associated with an increased risk of relapses.

After reviewing studies of vaccines in patients with MS, the MS Council for Clinical Practice Guidelines concluded in 2002 that the evidence supported strategies to minimize infections that can trigger relapses. The panel also concluded that the vaccines for influenza, hepatitis B, varicella, tetanus, and Bacillus Calmette–Guérin were safe for patients with MS. The council endorsed killed vaccines and recommended that neurologists wait for four to six weeks after the onset of a relapse before vaccinating a patient with MS. Physicians should be consulted, however, before administering a live vaccine to a patient receiving an immunosuppressive agent, the panel added.

Specific Vaccines and MS
Researchers also have examined the safety of specific vaccines in patients with MS. The seasonal influenza vaccine may be the best-studied vaccine in this population. The consensus is that the killed virus vaccine is safe, even for patients on a DMT, but that the live vaccine should be avoided.

Three vaccines have raised concerns for patients with MS. Several reports associated the hepatitis B vaccine with demyelinating episodes, but, after reviewing the evidence, the Institute of Medicine concluded that it was safe for patients with MS. Similarly, the literature contains reports of immune-mediated complications of the human papillomavirus (HPV) vaccine in patients with MS, but the vaccine is now accepted as safe in this population.

One case report has discouraged physicians from giving yellow fever vaccine to patients with MS. This vaccine was associated with increased clinical attacks and increased MRI lesion activity, although the report contained a small number of patients. The vaccine is contraindicated in patients who take immunosuppression or immunomodulatory therapies.

A large case–control study presented at the 66th Annual Meeting of the American Academy of Neurology included 780 patients with MS and 3,885 controls. The researchers found no association between an increased risk of demyelinating disease and the hepatitis B vaccine, the HPV vaccine, or any other vaccine. Younger individuals appeared to have an increased risk of CNS expression of disease during the first 30 days after vaccination, but the association was not linked to any specific vaccine. “The ultimate conclusion of this database study was that there was no need to change our current vaccine policy in MS,” said Dr. Coyle.

DMTs and Vaccinations
Researchers also have studied whether DMTs affect a patient’s response to vaccinations. Interferon betas are associated with normal humoral and cellular immune responses to the influenza vaccine. Investigators know of no negative effects of glatiramer acetate that relate to vaccines. Natalizumab is associated with normal humoral responses to the influenza, tetanus, and keyhole limpet hemocyanin vaccines. Researchers found an association between teriflunomide and normal immune responses to the influenza and rabies vaccines. No data about dimethyl fumarate’s effect on vaccine response exist, but the National MS Society does not recommend administering live vaccines to patients with MS who take this drug, said Dr. Coyle.

A pilot study indicated that alemtuzumab is associated with normal responses to the meningococcus, pneumococcus, and diphtheria–pertussis–tetanus vaccines in most individuals. The vaccine did not work, however, if patients were vaccinated within several months of their treatment cycle. “The recommendation for alemtuzumab is that you either vaccinate before you give the therapy, or you wait at least six months after the treatment cycle,” said Dr. Coyle. If a neurologist vaccinates the patient six months after the treatment cycle, he or she should measure the patient’s antibody levels about a month later to confirm that the vaccine is working, she added.

Of all DMTs, fingolimod appears to have the most influence on a patient’s response to vaccination. The drug decreases the humoral response to the influenza, tetanus, and pneumococcal vaccines. Before initiating fingolimod, a neurologist should screen the patient for VZV antibodies. If the results are negative or show a low titer of VZV antibodies, neurologists may vaccinate the patient before starting fingolimod. Initiation of therapy should be delayed a month after completion of the vaccination, said Dr. Coyle. Patients taking fingolimod should not receive a live vaccine, and post treatment vaccination should be delayed until two months after the drug is stopped, she added

—Erik Greb

Patients with relapsing-remitting multiple sclerosis who switched from an injectable disease-modifying therapy to orally administered fingolimod reported significantly greater treatment satisfaction as well as functional and quality of life outcomes than did those who took the same or a different injectable therapy in a phase IV, open-label, randomized trial.

The results of this trial, called EPOC (Evaluate Patient Outcomes), were similar to those reported for changes in activities of daily living according to the PRIMUS (Patient Reported Indices for Multiple Sclerosis) Activities scale in the double-blind, randomized TRANSFORMS trial that compared fingolimod (Gilenya) to intramuscular interferon beta-1a. However, these measurements did not reach statistical significance in EPOC, possibly because its 6-month duration was not long enough to detect differences, Dr. Edward Fox of Central Texas Neurology Consultants, Round Rock, and his colleagues reported on behalf of the EPOC study investigators.

"Our findings are consistent with those of studies in other diseases, such as thromboembolism prophylaxis, iron chelation, and oncology, which have also found greater levels of patient satisfaction and improved QOL associated with oral versus injectable therapies," the investigators wrote.

For the EPOC trial, investigators from 158 centers in the United States and Canada randomized 1,053 patients with relapsing-remitting MS to either fingolimod 0.5 mg once daily (790 patients) or an injectable disease-modifying therapy (iDMT; 263 patients). The iDMT options included interferon beta-1b subcutaneous 0.25 mg every other day (Betaseron), interferon beta-1a intramuscular 30 mcg once per week (Avonex), interferon beta-1a subcutaneous three times per week (Rebif), or glatiramer acetate subcutaneous 20 mg once daily (Copaxone). The patients had taken an iDMT for at least 6 months and had no washout period before making a switch. They had a mean duration of MS symptoms of 12 years and a mean Expanded Disability Status Scale score of 2.4 (Mult. Scler. Relat. Disord. 2014 July 3 [doi: 10.1016/j.msard.2014.06.005]).

At the time of randomization, most patients were taking glatiramer acetate (33%-35%), followed by intramuscular interferon beta-1a (23%-26%), subcutaneous interferon beta-1a (25% in each), and interferon beta-1b (16%-18%). The patients’ most commonly cited reasons for wishing to switch to a different therapy included mode of administration in 61%-62%, tolerability issues in 13%-14%, and physician-determined lack of efficacy in 12%-16%. Of the 263 patients who stayed on an iDMT, 26 switched to a different drug.

By 6 months, fingolimod-treated patients had significantly higher treatment satisfaction than did those who remained on an iDMT, based on the primary endpoint of difference between the groups on the change in the Global Satisfaction subscale score of the Treatment Satisfaction Questionnaire for Medication. They also reported significant improvements over patients who remained on an iDMT on secondary endpoints that measured changes on the Fatigue Severity Scale, the Beck Depression Inventory II, and the 36-item Short-Form Health Survey’s domains of physical health, bodily pain, vitality, social functioning, role limitation due to emotional problems, and general mental health. The two groups reported no statistically significant differences on changes in perceived activity limitations as measured by the PRIMUS Activities scale.

The physician-rated Clinical Global Impression of Improvement scores significantly favored fingolimod over iDMT (3.2 vs. 3.9, respectively), and although these scores were "in the range of only minimal improvement to no change in both the fingolimod and the iDMT groups, it is worth noting that the effect was measured early in the course of fingolimod treatment in this cohort of patients with long-standing MS," Dr. Fox and his associates wrote.

Adverse events occurred more often among patients who took fingolimod than in those who took an iDMT (79% vs. 62%, respectively), and the most common of these for fingolimod-treated patients were headache and fatigue at 12% each. There was no difference in the incidence of serious adverse events between patients who took fingolimod or an iDMT (4% vs. 2%, respectively), including MS relapse (0.6% vs. 0.8%) and lymphopenia (0.3% vs. 0%). Overall, 41 fingolimod-treated patients discontinued treatment because of an adverse event, compared with 4 iDMT-treated patients.

"Notably, the absence of a washout period between cessation of the iDMT and initiation of fingolimod did not appear to be associated with deleterious additive immune system effects," the investigators wrote.

The study was funded by Novartis, which markets fingolimod. Many authors reported financial relationships with Novartis as well as with the marketers of Betaseron (Bayer HealthCare), Avonex (Biogen Idec), Rebif (EMD Serono and Pfizer), and Copaxone (Teva Neuroscience). Four authors are or were employees of Novartis.

jevans@frontlinemedcom.com

Patients with relapsing-remitting multiple sclerosis who switched from an injectable disease-modifying therapy to orally administered fingolimod reported significantly greater treatment satisfaction as well as functional and quality of life outcomes than did those who took the same or a different injectable therapy in a phase IV, open-label, randomized trial.

The results of this trial, called EPOC (Evaluate Patient Outcomes), were similar to those reported for changes in activities of daily living according to the PRIMUS (Patient Reported Indices for Multiple Sclerosis) Activities scale in the double-blind, randomized TRANSFORMS trial that compared fingolimod (Gilenya) to intramuscular interferon beta-1a. However, these measurements did not reach statistical significance in EPOC, possibly because its 6-month duration was not long enough to detect differences, Dr. Edward Fox of Central Texas Neurology Consultants, Round Rock, and his colleagues reported on behalf of the EPOC study investigators.

"Our findings are consistent with those of studies in other diseases, such as thromboembolism prophylaxis, iron chelation, and oncology, which have also found greater levels of patient satisfaction and improved QOL associated with oral versus injectable therapies," the investigators wrote.

For the EPOC trial, investigators from 158 centers in the United States and Canada randomized 1,053 patients with relapsing-remitting MS to either fingolimod 0.5 mg once daily (790 patients) or an injectable disease-modifying therapy (iDMT; 263 patients). The iDMT options included interferon beta-1b subcutaneous 0.25 mg every other day (Betaseron), interferon beta-1a intramuscular 30 mcg once per week (Avonex), interferon beta-1a subcutaneous three times per week (Rebif), or glatiramer acetate subcutaneous 20 mg once daily (Copaxone). The patients had taken an iDMT for at least 6 months and had no washout period before making a switch. They had a mean duration of MS symptoms of 12 years and a mean Expanded Disability Status Scale score of 2.4 (Mult. Scler. Relat. Disord. 2014 July 3 [doi: 10.1016/j.msard.2014.06.005]).

At the time of randomization, most patients were taking glatiramer acetate (33%-35%), followed by intramuscular interferon beta-1a (23%-26%), subcutaneous interferon beta-1a (25% in each), and interferon beta-1b (16%-18%). The patients’ most commonly cited reasons for wishing to switch to a different therapy included mode of administration in 61%-62%, tolerability issues in 13%-14%, and physician-determined lack of efficacy in 12%-16%. Of the 263 patients who stayed on an iDMT, 26 switched to a different drug.

By 6 months, fingolimod-treated patients had significantly higher treatment satisfaction than did those who remained on an iDMT, based on the primary endpoint of difference between the groups on the change in the Global Satisfaction subscale score of the Treatment Satisfaction Questionnaire for Medication. They also reported significant improvements over patients who remained on an iDMT on secondary endpoints that measured changes on the Fatigue Severity Scale, the Beck Depression Inventory II, and the 36-item Short-Form Health Survey’s domains of physical health, bodily pain, vitality, social functioning, role limitation due to emotional problems, and general mental health. The two groups reported no statistically significant differences on changes in perceived activity limitations as measured by the PRIMUS Activities scale.

The physician-rated Clinical Global Impression of Improvement scores significantly favored fingolimod over iDMT (3.2 vs. 3.9, respectively), and although these scores were "in the range of only minimal improvement to no change in both the fingolimod and the iDMT groups, it is worth noting that the effect was measured early in the course of fingolimod treatment in this cohort of patients with long-standing MS," Dr. Fox and his associates wrote.

Adverse events occurred more often among patients who took fingolimod than in those who took an iDMT (79% vs. 62%, respectively), and the most common of these for fingolimod-treated patients were headache and fatigue at 12% each. There was no difference in the incidence of serious adverse events between patients who took fingolimod or an iDMT (4% vs. 2%, respectively), including MS relapse (0.6% vs. 0.8%) and lymphopenia (0.3% vs. 0%). Overall, 41 fingolimod-treated patients discontinued treatment because of an adverse event, compared with 4 iDMT-treated patients.

"Notably, the absence of a washout period between cessation of the iDMT and initiation of fingolimod did not appear to be associated with deleterious additive immune system effects," the investigators wrote.

The study was funded by Novartis, which markets fingolimod. Many authors reported financial relationships with Novartis as well as with the marketers of Betaseron (Bayer HealthCare), Avonex (Biogen Idec), Rebif (EMD Serono and Pfizer), and Copaxone (Teva Neuroscience). Four authors are or were employees of Novartis.

jevans@frontlinemedcom.com

Patients with relapsing-remitting multiple sclerosis who switched from an injectable disease-modifying therapy to orally administered fingolimod reported significantly greater treatment satisfaction as well as functional and quality of life outcomes than did those who took the same or a different injectable therapy in a phase IV, open-label, randomized trial.

The results of this trial, called EPOC (Evaluate Patient Outcomes), were similar to those reported for changes in activities of daily living according to the PRIMUS (Patient Reported Indices for Multiple Sclerosis) Activities scale in the double-blind, randomized TRANSFORMS trial that compared fingolimod (Gilenya) to intramuscular interferon beta-1a. However, these measurements did not reach statistical significance in EPOC, possibly because its 6-month duration was not long enough to detect differences, Dr. Edward Fox of Central Texas Neurology Consultants, Round Rock, and his colleagues reported on behalf of the EPOC study investigators.

"Our findings are consistent with those of studies in other diseases, such as thromboembolism prophylaxis, iron chelation, and oncology, which have also found greater levels of patient satisfaction and improved QOL associated with oral versus injectable therapies," the investigators wrote.

For the EPOC trial, investigators from 158 centers in the United States and Canada randomized 1,053 patients with relapsing-remitting MS to either fingolimod 0.5 mg once daily (790 patients) or an injectable disease-modifying therapy (iDMT; 263 patients). The iDMT options included interferon beta-1b subcutaneous 0.25 mg every other day (Betaseron), interferon beta-1a intramuscular 30 mcg once per week (Avonex), interferon beta-1a subcutaneous three times per week (Rebif), or glatiramer acetate subcutaneous 20 mg once daily (Copaxone). The patients had taken an iDMT for at least 6 months and had no washout period before making a switch. They had a mean duration of MS symptoms of 12 years and a mean Expanded Disability Status Scale score of 2.4 (Mult. Scler. Relat. Disord. 2014 July 3 [doi: 10.1016/j.msard.2014.06.005]).

At the time of randomization, most patients were taking glatiramer acetate (33%-35%), followed by intramuscular interferon beta-1a (23%-26%), subcutaneous interferon beta-1a (25% in each), and interferon beta-1b (16%-18%). The patients’ most commonly cited reasons for wishing to switch to a different therapy included mode of administration in 61%-62%, tolerability issues in 13%-14%, and physician-determined lack of efficacy in 12%-16%. Of the 263 patients who stayed on an iDMT, 26 switched to a different drug.

By 6 months, fingolimod-treated patients had significantly higher treatment satisfaction than did those who remained on an iDMT, based on the primary endpoint of difference between the groups on the change in the Global Satisfaction subscale score of the Treatment Satisfaction Questionnaire for Medication. They also reported significant improvements over patients who remained on an iDMT on secondary endpoints that measured changes on the Fatigue Severity Scale, the Beck Depression Inventory II, and the 36-item Short-Form Health Survey’s domains of physical health, bodily pain, vitality, social functioning, role limitation due to emotional problems, and general mental health. The two groups reported no statistically significant differences on changes in perceived activity limitations as measured by the PRIMUS Activities scale.

The physician-rated Clinical Global Impression of Improvement scores significantly favored fingolimod over iDMT (3.2 vs. 3.9, respectively), and although these scores were "in the range of only minimal improvement to no change in both the fingolimod and the iDMT groups, it is worth noting that the effect was measured early in the course of fingolimod treatment in this cohort of patients with long-standing MS," Dr. Fox and his associates wrote.

Adverse events occurred more often among patients who took fingolimod than in those who took an iDMT (79% vs. 62%, respectively), and the most common of these for fingolimod-treated patients were headache and fatigue at 12% each. There was no difference in the incidence of serious adverse events between patients who took fingolimod or an iDMT (4% vs. 2%, respectively), including MS relapse (0.6% vs. 0.8%) and lymphopenia (0.3% vs. 0%). Overall, 41 fingolimod-treated patients discontinued treatment because of an adverse event, compared with 4 iDMT-treated patients.

"Notably, the absence of a washout period between cessation of the iDMT and initiation of fingolimod did not appear to be associated with deleterious additive immune system effects," the investigators wrote.

The study was funded by Novartis, which markets fingolimod. Many authors reported financial relationships with Novartis as well as with the marketers of Betaseron (Bayer HealthCare), Avonex (Biogen Idec), Rebif (EMD Serono and Pfizer), and Copaxone (Teva Neuroscience). Four authors are or were employees of Novartis.

jevans@frontlinemedcom.com

The risk of disease reactivation rises in adults with multiple sclerosis who discontinue natalizumab treatment after 24 doses, according to findings from the prospective, multicenter, observational TY-STOP Study.

In an intent-to-treat analysis, disease activity was significantly lower among 43 patients who continued natalizumab treatment, compared with 81 who had interrupted treatment (odds ratios, 0.33 for clinical activity and 0.35 for radiologic activity). In an as-treated analysis, clinical disease activity was more than three times higher in 16 patients who switched treatments (OR, 3.28), and more than four times higher in natalizumab quitters (OR, 4.40), compared with 35 patients who continued on natalizumab. Dr. Marinella Clerico of the University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy, and her colleagues reported the findings online June 30 in JAMA Neurology.

One patient who discontinued treatment developed progressive multifocal leukoencephalopathy (PML) during the observation period, but recovered completely (JAMA Neurol. 2014 [doi:10.1001/jamaneurol.2014.1200]).

Continuing natalizumab seems to be the most efficacious therapeutic strategy in those who have already received 24 doses and who must – according to a "meticulous risk management plan" implemented by the European Medicines Agency in the wake of increased incidence of PML among natalizumab users – renew consent to continue treatment after 24 doses. However, given the risk of PML, the decision to continue treatment should take into account the risk of disease reactivation associated with discontinuation as well as the risk of PML with continuation, and treatment should be continued, along with meticulous monitoring for PML, in all patients in whom risk is not considered too high, they concluded.

Dr. Clerico reported receiving travel grants from Merck Serono and Biogen Idec. Other authors also made financial disclosures, the details of which are available with the full text of the article at jamaneurology.com.

The risk of disease reactivation rises in adults with multiple sclerosis who discontinue natalizumab treatment after 24 doses, according to findings from the prospective, multicenter, observational TY-STOP Study.

In an intent-to-treat analysis, disease activity was significantly lower among 43 patients who continued natalizumab treatment, compared with 81 who had interrupted treatment (odds ratios, 0.33 for clinical activity and 0.35 for radiologic activity). In an as-treated analysis, clinical disease activity was more than three times higher in 16 patients who switched treatments (OR, 3.28), and more than four times higher in natalizumab quitters (OR, 4.40), compared with 35 patients who continued on natalizumab. Dr. Marinella Clerico of the University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy, and her colleagues reported the findings online June 30 in JAMA Neurology.

One patient who discontinued treatment developed progressive multifocal leukoencephalopathy (PML) during the observation period, but recovered completely (JAMA Neurol. 2014 [doi:10.1001/jamaneurol.2014.1200]).

Continuing natalizumab seems to be the most efficacious therapeutic strategy in those who have already received 24 doses and who must – according to a "meticulous risk management plan" implemented by the European Medicines Agency in the wake of increased incidence of PML among natalizumab users – renew consent to continue treatment after 24 doses. However, given the risk of PML, the decision to continue treatment should take into account the risk of disease reactivation associated with discontinuation as well as the risk of PML with continuation, and treatment should be continued, along with meticulous monitoring for PML, in all patients in whom risk is not considered too high, they concluded.

Dr. Clerico reported receiving travel grants from Merck Serono and Biogen Idec. Other authors also made financial disclosures, the details of which are available with the full text of the article at jamaneurology.com.

The risk of disease reactivation rises in adults with multiple sclerosis who discontinue natalizumab treatment after 24 doses, according to findings from the prospective, multicenter, observational TY-STOP Study.

In an intent-to-treat analysis, disease activity was significantly lower among 43 patients who continued natalizumab treatment, compared with 81 who had interrupted treatment (odds ratios, 0.33 for clinical activity and 0.35 for radiologic activity). In an as-treated analysis, clinical disease activity was more than three times higher in 16 patients who switched treatments (OR, 3.28), and more than four times higher in natalizumab quitters (OR, 4.40), compared with 35 patients who continued on natalizumab. Dr. Marinella Clerico of the University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy, and her colleagues reported the findings online June 30 in JAMA Neurology.

One patient who discontinued treatment developed progressive multifocal leukoencephalopathy (PML) during the observation period, but recovered completely (JAMA Neurol. 2014 [doi:10.1001/jamaneurol.2014.1200]).

Continuing natalizumab seems to be the most efficacious therapeutic strategy in those who have already received 24 doses and who must – according to a "meticulous risk management plan" implemented by the European Medicines Agency in the wake of increased incidence of PML among natalizumab users – renew consent to continue treatment after 24 doses. However, given the risk of PML, the decision to continue treatment should take into account the risk of disease reactivation associated with discontinuation as well as the risk of PML with continuation, and treatment should be continued, along with meticulous monitoring for PML, in all patients in whom risk is not considered too high, they concluded.

Dr. Clerico reported receiving travel grants from Merck Serono and Biogen Idec. Other authors also made financial disclosures, the details of which are available with the full text of the article at jamaneurology.com.

Contrary to findings from previous studies, serologic testing for KIR4.1-specific IgG did not help in the diagnosis of multiple sclerosis in a new comparative study.

"No neural autoantigen has been clinically validated as a target of immunoglobulins in serum or CSF [cerebrospinal fluid] in multiple sclerosis," researchers led by Adipong Brickshawana, Ph.D., wrote July 7 in the Lancet Neurology. "The absence of a disease specific biomarker to aid multiple sclerosis diagnosis makes therapeutic trial design and outcome interpretation difficult," they said.

In their own analysis, the researchers determined that the lack of patient-derived IgG reactivity with KIR4.1 "in plasma membrane, cytoplasm, or endoplasmic reticulum of cultured glia argues against antigenic differences in recombinant and native glial KIR4.1." The finding runs counter to 2012 study that used enzyme-linked immunosorbent assay (ELISA). It found that serum antibodies against KIR4.1 were detected in 47% of 397 patients with multiple sclerosis, 1% of 329 patients with other neurologic diseases, and none of the 59 healthy donors (N. Engl. J. Med. 2012;367:115-23).

For the current analysis, Dr. Brickshawana of the departments of immunology and neurology at the Mayo Clinic, Rochester, Minn., and his associates used ELISA with a KIR4.1 peptide to test archival serum from 229 population-based and 57-clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, as well as CSF from 25 patients with multiple sclerosis and 22 disease controls (Lancet Neurol. 2014 July 7 [doi:10/1016/S1474-4422(14)70141-3]).

The researchers used cell-based immunofluorescence and immunoprecipitation to test all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1. They also looked for KIR4.1 immunoreactivity in archival brain samples from 15 patients with multiple sclerosis confirmed by histopathology, as well as from three controls with non-neurologic diseases.

Of the serum samples collected, only three from the 286 patients with multiple sclerosis (1.05%) and two from the 208 controls (0.96%) demonstrated KIR4.1 reactivity on ELISA, while none of the CSF samples from patients or controls demonstrated KIR4.1 reactivity. In addition, the researchers did not detect KIR4.1 loss from glia in supratentorial white-matter lesions of archival multiple sclerosis cases.

"Our findings provide neither serological nor neuropathological evidence to lend support to the idea that autoantibodies target glial KIR4.1 K⁺ channels in patients with multiple sclerosis," the researchers concluded.

Dr. Brickshawana and his colleagues went on to note that different analytical approaches "might, in part, explain these contradictory findings. However, before drawing conclusions, it is essential that KIR4.1 immunoreactivity is examined relative to control white-matter expression as we did in the current study."

The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic’s Robert and Arlene Kogod Center on Aging.

dbrunk@frontlinemedcom.com

Contrary to findings from previous studies, serologic testing for KIR4.1-specific IgG did not help in the diagnosis of multiple sclerosis in a new comparative study.

"No neural autoantigen has been clinically validated as a target of immunoglobulins in serum or CSF [cerebrospinal fluid] in multiple sclerosis," researchers led by Adipong Brickshawana, Ph.D., wrote July 7 in the Lancet Neurology. "The absence of a disease specific biomarker to aid multiple sclerosis diagnosis makes therapeutic trial design and outcome interpretation difficult," they said.

In their own analysis, the researchers determined that the lack of patient-derived IgG reactivity with KIR4.1 "in plasma membrane, cytoplasm, or endoplasmic reticulum of cultured glia argues against antigenic differences in recombinant and native glial KIR4.1." The finding runs counter to 2012 study that used enzyme-linked immunosorbent assay (ELISA). It found that serum antibodies against KIR4.1 were detected in 47% of 397 patients with multiple sclerosis, 1% of 329 patients with other neurologic diseases, and none of the 59 healthy donors (N. Engl. J. Med. 2012;367:115-23).

For the current analysis, Dr. Brickshawana of the departments of immunology and neurology at the Mayo Clinic, Rochester, Minn., and his associates used ELISA with a KIR4.1 peptide to test archival serum from 229 population-based and 57-clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, as well as CSF from 25 patients with multiple sclerosis and 22 disease controls (Lancet Neurol. 2014 July 7 [doi:10/1016/S1474-4422(14)70141-3]).

The researchers used cell-based immunofluorescence and immunoprecipitation to test all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1. They also looked for KIR4.1 immunoreactivity in archival brain samples from 15 patients with multiple sclerosis confirmed by histopathology, as well as from three controls with non-neurologic diseases.

Of the serum samples collected, only three from the 286 patients with multiple sclerosis (1.05%) and two from the 208 controls (0.96%) demonstrated KIR4.1 reactivity on ELISA, while none of the CSF samples from patients or controls demonstrated KIR4.1 reactivity. In addition, the researchers did not detect KIR4.1 loss from glia in supratentorial white-matter lesions of archival multiple sclerosis cases.

"Our findings provide neither serological nor neuropathological evidence to lend support to the idea that autoantibodies target glial KIR4.1 K⁺ channels in patients with multiple sclerosis," the researchers concluded.

Dr. Brickshawana and his colleagues went on to note that different analytical approaches "might, in part, explain these contradictory findings. However, before drawing conclusions, it is essential that KIR4.1 immunoreactivity is examined relative to control white-matter expression as we did in the current study."

The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic’s Robert and Arlene Kogod Center on Aging.

dbrunk@frontlinemedcom.com

Contrary to findings from previous studies, serologic testing for KIR4.1-specific IgG did not help in the diagnosis of multiple sclerosis in a new comparative study.

"No neural autoantigen has been clinically validated as a target of immunoglobulins in serum or CSF [cerebrospinal fluid] in multiple sclerosis," researchers led by Adipong Brickshawana, Ph.D., wrote July 7 in the Lancet Neurology. "The absence of a disease specific biomarker to aid multiple sclerosis diagnosis makes therapeutic trial design and outcome interpretation difficult," they said.

In their own analysis, the researchers determined that the lack of patient-derived IgG reactivity with KIR4.1 "in plasma membrane, cytoplasm, or endoplasmic reticulum of cultured glia argues against antigenic differences in recombinant and native glial KIR4.1." The finding runs counter to 2012 study that used enzyme-linked immunosorbent assay (ELISA). It found that serum antibodies against KIR4.1 were detected in 47% of 397 patients with multiple sclerosis, 1% of 329 patients with other neurologic diseases, and none of the 59 healthy donors (N. Engl. J. Med. 2012;367:115-23).

For the current analysis, Dr. Brickshawana of the departments of immunology and neurology at the Mayo Clinic, Rochester, Minn., and his associates used ELISA with a KIR4.1 peptide to test archival serum from 229 population-based and 57-clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, as well as CSF from 25 patients with multiple sclerosis and 22 disease controls (Lancet Neurol. 2014 July 7 [doi:10/1016/S1474-4422(14)70141-3]).

The researchers used cell-based immunofluorescence and immunoprecipitation to test all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1. They also looked for KIR4.1 immunoreactivity in archival brain samples from 15 patients with multiple sclerosis confirmed by histopathology, as well as from three controls with non-neurologic diseases.

Of the serum samples collected, only three from the 286 patients with multiple sclerosis (1.05%) and two from the 208 controls (0.96%) demonstrated KIR4.1 reactivity on ELISA, while none of the CSF samples from patients or controls demonstrated KIR4.1 reactivity. In addition, the researchers did not detect KIR4.1 loss from glia in supratentorial white-matter lesions of archival multiple sclerosis cases.

"Our findings provide neither serological nor neuropathological evidence to lend support to the idea that autoantibodies target glial KIR4.1 K⁺ channels in patients with multiple sclerosis," the researchers concluded.

Dr. Brickshawana and his colleagues went on to note that different analytical approaches "might, in part, explain these contradictory findings. However, before drawing conclusions, it is essential that KIR4.1 immunoreactivity is examined relative to control white-matter expression as we did in the current study."

The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic’s Robert and Arlene Kogod Center on Aging.

dbrunk@frontlinemedcom.com

PHILADELPHIA—Alfacalcidol, a synthetic analog of vitamin D, significantly reduces fatigue related to multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug also may result in significant improvements in psychologic and social quality of life. No serious adverse events are associated with alfacalcidol, which appears to have a rate of adverse events similar to that of placebo.

In a six-month study, alfacalcidol reduced the number of acute relapses in patients with MS. This result suggests that fatigue, like relapses, is a symptom of disease activity, said Anat Achiron, MD, PhD, Director of the MS Center at the Sheba Medical Center in Tel Hashomer, Israel. “By decreasing fatigue and relapses, you can achieve the same goal,” she added.

Comparing Alfacalcido With Placebo
The trial was designed as a two-stage process to enrich the study population with patients with MS whose fatigue is significant. Dr. Achiron and colleagues administered the Fatigue Severity Scale to 600 patients with relapsing-remitting MS to analyze the effect of alfacalcidol on MS-related fatigue. A total of 500 patients responded to the questionnaire, and 259 patients who gave a score of 3 or higher to the ninth item (ie, “Fatigue interferes with my work, family, or social life”) were included in the second stage of enrollment.

A total of 158 patients between ages 18 and 55 who had an Expanded Disability Status Scale (EDSS) score of 5 or lower and a Fatigue Impact Scale (FIS) score of 40 or higher were eligible. Of these patients, 80 were randomized to receive 1 µg/day of alfacalcidol, and 78 were randomized to placebo. All patients completed the FIS and RAYS quality of life questionnaire at baseline. Patients were treated for six months, at which point they completed the FIS and RAYS questionnaires again. The researchers conducted follow-up visits with the patients two months after the cessation of treatment.

The primary end point was improvement in FIS score, which was defined as a 30% decrease. The secondary end points were change in the RAYS quality of life scale, change in EDSS score, and the number of acute relapses.

Reduced Fatigue and Relapses
The investigators found no significant differences at baseline between the study groups with respect to age, gender distribution, age of disease onset, EDSS score, and duration of fatigue. The level of fatigue was high at baseline; mean FIS score was 80 in the treatment group and 78 among controls, “suggesting that the patients had significant fatigue that affected their lives,” said Dr. Achiron. At six months, the relative FIS score decreased for all study participants. Only patients who received alfacalcidol, however, had a decrease in FIS score of at least 30%. FIS score was reduced by a mean of 41.6% among alfacalcidol-treated patients. The reduction was most noticeable on the cognitive subscale of FIS, compared with the physical and social subscales, said Dr. Achiron.

RAYS quality of life score improved at six months for patients treated with alfacalcidol. Physical quality of life did not change, but psychologic and social quality of life improved significantly in patients who received alfacalcidol. EDSS score did not change for any participants.

In addition, the number of relapses was significantly lower among participants receiving alfacalcidol, and the percentage of relapse-free patients was higher in the treatment group than in the control group. The difference between groups in the number of relapses was already evident at four months. The association between alfacalcidol and a reduction in relapses is consistent with literature suggesting that vitamin D enhances the apoptosis of autoreactive T cells, said Dr. Achiron.

“Alfacalcidol is a safe and effective treatment strategy for treating fatigue in MS,” she concluded.

—Erik Greb

PHILADELPHIA—Alfacalcidol, a synthetic analog of vitamin D, significantly reduces fatigue related to multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug also may result in significant improvements in psychologic and social quality of life. No serious adverse events are associated with alfacalcidol, which appears to have a rate of adverse events similar to that of placebo.

In a six-month study, alfacalcidol reduced the number of acute relapses in patients with MS. This result suggests that fatigue, like relapses, is a symptom of disease activity, said Anat Achiron, MD, PhD, Director of the MS Center at the Sheba Medical Center in Tel Hashomer, Israel. “By decreasing fatigue and relapses, you can achieve the same goal,” she added.

Comparing Alfacalcido With Placebo
The trial was designed as a two-stage process to enrich the study population with patients with MS whose fatigue is significant. Dr. Achiron and colleagues administered the Fatigue Severity Scale to 600 patients with relapsing-remitting MS to analyze the effect of alfacalcidol on MS-related fatigue. A total of 500 patients responded to the questionnaire, and 259 patients who gave a score of 3 or higher to the ninth item (ie, “Fatigue interferes with my work, family, or social life”) were included in the second stage of enrollment.

A total of 158 patients between ages 18 and 55 who had an Expanded Disability Status Scale (EDSS) score of 5 or lower and a Fatigue Impact Scale (FIS) score of 40 or higher were eligible. Of these patients, 80 were randomized to receive 1 µg/day of alfacalcidol, and 78 were randomized to placebo. All patients completed the FIS and RAYS quality of life questionnaire at baseline. Patients were treated for six months, at which point they completed the FIS and RAYS questionnaires again. The researchers conducted follow-up visits with the patients two months after the cessation of treatment.

The primary end point was improvement in FIS score, which was defined as a 30% decrease. The secondary end points were change in the RAYS quality of life scale, change in EDSS score, and the number of acute relapses.

Reduced Fatigue and Relapses
The investigators found no significant differences at baseline between the study groups with respect to age, gender distribution, age of disease onset, EDSS score, and duration of fatigue. The level of fatigue was high at baseline; mean FIS score was 80 in the treatment group and 78 among controls, “suggesting that the patients had significant fatigue that affected their lives,” said Dr. Achiron. At six months, the relative FIS score decreased for all study participants. Only patients who received alfacalcidol, however, had a decrease in FIS score of at least 30%. FIS score was reduced by a mean of 41.6% among alfacalcidol-treated patients. The reduction was most noticeable on the cognitive subscale of FIS, compared with the physical and social subscales, said Dr. Achiron.

RAYS quality of life score improved at six months for patients treated with alfacalcidol. Physical quality of life did not change, but psychologic and social quality of life improved significantly in patients who received alfacalcidol. EDSS score did not change for any participants.

In addition, the number of relapses was significantly lower among participants receiving alfacalcidol, and the percentage of relapse-free patients was higher in the treatment group than in the control group. The difference between groups in the number of relapses was already evident at four months. The association between alfacalcidol and a reduction in relapses is consistent with literature suggesting that vitamin D enhances the apoptosis of autoreactive T cells, said Dr. Achiron.

“Alfacalcidol is a safe and effective treatment strategy for treating fatigue in MS,” she concluded.

—Erik Greb

PHILADELPHIA—Alfacalcidol, a synthetic analog of vitamin D, significantly reduces fatigue related to multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The drug also may result in significant improvements in psychologic and social quality of life. No serious adverse events are associated with alfacalcidol, which appears to have a rate of adverse events similar to that of placebo.

In a six-month study, alfacalcidol reduced the number of acute relapses in patients with MS. This result suggests that fatigue, like relapses, is a symptom of disease activity, said Anat Achiron, MD, PhD, Director of the MS Center at the Sheba Medical Center in Tel Hashomer, Israel. “By decreasing fatigue and relapses, you can achieve the same goal,” she added.

Comparing Alfacalcido With Placebo
The trial was designed as a two-stage process to enrich the study population with patients with MS whose fatigue is significant. Dr. Achiron and colleagues administered the Fatigue Severity Scale to 600 patients with relapsing-remitting MS to analyze the effect of alfacalcidol on MS-related fatigue. A total of 500 patients responded to the questionnaire, and 259 patients who gave a score of 3 or higher to the ninth item (ie, “Fatigue interferes with my work, family, or social life”) were included in the second stage of enrollment.

A total of 158 patients between ages 18 and 55 who had an Expanded Disability Status Scale (EDSS) score of 5 or lower and a Fatigue Impact Scale (FIS) score of 40 or higher were eligible. Of these patients, 80 were randomized to receive 1 µg/day of alfacalcidol, and 78 were randomized to placebo. All patients completed the FIS and RAYS quality of life questionnaire at baseline. Patients were treated for six months, at which point they completed the FIS and RAYS questionnaires again. The researchers conducted follow-up visits with the patients two months after the cessation of treatment.

The primary end point was improvement in FIS score, which was defined as a 30% decrease. The secondary end points were change in the RAYS quality of life scale, change in EDSS score, and the number of acute relapses.

Reduced Fatigue and Relapses
The investigators found no significant differences at baseline between the study groups with respect to age, gender distribution, age of disease onset, EDSS score, and duration of fatigue. The level of fatigue was high at baseline; mean FIS score was 80 in the treatment group and 78 among controls, “suggesting that the patients had significant fatigue that affected their lives,” said Dr. Achiron. At six months, the relative FIS score decreased for all study participants. Only patients who received alfacalcidol, however, had a decrease in FIS score of at least 30%. FIS score was reduced by a mean of 41.6% among alfacalcidol-treated patients. The reduction was most noticeable on the cognitive subscale of FIS, compared with the physical and social subscales, said Dr. Achiron.

RAYS quality of life score improved at six months for patients treated with alfacalcidol. Physical quality of life did not change, but psychologic and social quality of life improved significantly in patients who received alfacalcidol. EDSS score did not change for any participants.

In addition, the number of relapses was significantly lower among participants receiving alfacalcidol, and the percentage of relapse-free patients was higher in the treatment group than in the control group. The difference between groups in the number of relapses was already evident at four months. The association between alfacalcidol and a reduction in relapses is consistent with literature suggesting that vitamin D enhances the apoptosis of autoreactive T cells, said Dr. Achiron.

“Alfacalcidol is a safe and effective treatment strategy for treating fatigue in MS,” she concluded.

—Erik Greb

There is a growing social and medical impetus to legalize cannabis not only for recreational use, but also for the treatment of neurologic disorders such as multiple sclerosis (MS). Although some studies have shown that cannabis may relieve spasticity, pain, and other symptoms in patients with MS, a new study by Pavisian et al sounds a cautionary note. The authors suggest that cannabis further compromises a brain already impaired from tissue damage in MS. One reason that the authors found functional MRI changes, but not structural MRI changes, might be that physiologic changes occurred before structural changes, which would not be unexpected. In addition, smoking may be a factor in MS worsening. Could smoking cigarettes rather than cannabis be the reason for the cognitive change among study participants? In the end, these findings suggest that cannabis may be a double-edged sword in MS, and possibly in other brain disorders. Further testing, including a prospective study of patients randomized to smoking cannabis or placebo, would be an important step toward confirming Pavisian’s results.

—Stuart D. Cook, MD
Professor of Neurology, Department of Neurosciences,
Rutgers, the State University of New Jersey,
New Jersey Medical School,
Newark, NJ

There is a growing social and medical impetus to legalize cannabis not only for recreational use, but also for the treatment of neurologic disorders such as multiple sclerosis (MS). Although some studies have shown that cannabis may relieve spasticity, pain, and other symptoms in patients with MS, a new study by Pavisian et al sounds a cautionary note. The authors suggest that cannabis further compromises a brain already impaired from tissue damage in MS. One reason that the authors found functional MRI changes, but not structural MRI changes, might be that physiologic changes occurred before structural changes, which would not be unexpected. In addition, smoking may be a factor in MS worsening. Could smoking cigarettes rather than cannabis be the reason for the cognitive change among study participants? In the end, these findings suggest that cannabis may be a double-edged sword in MS, and possibly in other brain disorders. Further testing, including a prospective study of patients randomized to smoking cannabis or placebo, would be an important step toward confirming Pavisian’s results.

—Stuart D. Cook, MD
Professor of Neurology, Department of Neurosciences,
Rutgers, the State University of New Jersey,
New Jersey Medical School,
Newark, NJ

There is a growing social and medical impetus to legalize cannabis not only for recreational use, but also for the treatment of neurologic disorders such as multiple sclerosis (MS). Although some studies have shown that cannabis may relieve spasticity, pain, and other symptoms in patients with MS, a new study by Pavisian et al sounds a cautionary note. The authors suggest that cannabis further compromises a brain already impaired from tissue damage in MS. One reason that the authors found functional MRI changes, but not structural MRI changes, might be that physiologic changes occurred before structural changes, which would not be unexpected. In addition, smoking may be a factor in MS worsening. Could smoking cigarettes rather than cannabis be the reason for the cognitive change among study participants? In the end, these findings suggest that cannabis may be a double-edged sword in MS, and possibly in other brain disorders. Further testing, including a prospective study of patients randomized to smoking cannabis or placebo, would be an important step toward confirming Pavisian’s results.

—Stuart D. Cook, MD
Professor of Neurology, Department of Neurosciences,
Rutgers, the State University of New Jersey,
New Jersey Medical School,
Newark, NJ

DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.

In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.

Whitney McKnight/Frontline Medical News

"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."

The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.

No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.

For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.

"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."

Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.

In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.

Whitney McKnight/Frontline Medical News

"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."

The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.

No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.

For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.

"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."

Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.

In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.

Whitney McKnight/Frontline Medical News

"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."

The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.

No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.

For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.

"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."

Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.

At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.

Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.

"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.

The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).

During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.

"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.

The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.

The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.

Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.

At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.

Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.

"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.

The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).

During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.

"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.

The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.

The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.

Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.

At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.

Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.

"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.

The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).

During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.

"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.

The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.

The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.

Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight