Multiple Sclerosis

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To read the accompanying article, please click here.

To read the accompanying article, please click here.

The Food and Drug Administration has approved a new, twice-daily oral medication, dimethyl fumarate, for relapsing-remitting multiple sclerosis.

The drug, to be marketed as Tecfidera, is thought to defend the brain against oxidative stress, and experimental evidence has suggested that it may also act both as an anti-inflammatory and as a neuroprotective agent.

Tecfidera joins a host of already approved medications for MS. Two forms of interferon beta-1a (Avonex and Rebif) and two forms of interferon beta-1b (Betaseron and Extavia) have been approved for the relapsing-remitting form, as has glatiramer acetate (Copaxone), fingolimod (Gilenya), and teriflunomide (Aubagio). Natalizumab (Tysabri) is approved for relapsing-remitting MS, but with restrictions. Mitoxantrone (Novantrone) is approved for secondary progressive, progressive-relapsing, and worsening relapsing-remitting MS, according to the National MS Society. Dalfampridine (Ampyra) is approved to improve walking in individuals with MS.

"No drug provides a cure for multiple sclerosis, so it is important to have a variety of treatment options available for patients," said Dr. Russell Katz, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.

According to the FDA, MS is among the most common causes of neurologic disability in young adults and occurs more frequently in women than men. Some 400,000 Americans are living with the condition, and the relapsing-remitting form is the most common. That is characterized by episodes of worsening function, followed by recovery periods. But recovery periods become less complete over time, leading to progressive decline in function and increased disability.

Dimethyl fumarate was approved based on results from two phase III trials that enrolled more than 2,600 patients: DEFINE and CONFIRM. DEFINE data were originally reported at the Fourth Cooperative Meeting on Multiple Sclerosis in 2011 and the CONFIRM data were reported at the Joint Congress of ECTRIMS/ACTRIMS in 2012.

According to Biogen Idec, which makes dimethyl fumarate, relapses were reduced by 49% in patients taking the drug in the DEFINE trial, and disability by 38%. Relapses declined by 34% in the CONFIRM study. In both trials, dimethyl fumarate significantly reduced lesions in the brain, when compared with placebo.

"In clinical trials, patients treated with dimethyl fumarate had less disease activity when compared to patients on placebo – whether they were in the early stages of MS or had more established disease," said Dr. Robert Fox, medical director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic, in a Biogen statement. Dr. Fox was the lead investigator of the CONFIRM study, and is a paid adviser for Biogen Idec for projects not related to dimethyl fumarate. "This drug provides physicians with an important additional treatment option for their patients across the MS spectrum," Dr. Fox said.

The FDA said that dimethyl fumarate decreases lymphocyte counts, but that there was no evidence of an increase in infections in patients taking the drug in trials. The agency recommends monitoring lymphocyte counts before starting therapy, and annually thereafter. Flushing and gastrointestinal problems were the most common adverse reactions.

Biogen said the drug would be available in a matter of days. The recommended starting dose is 120 mg twice a day orally. After a week, the recommended dose increases to 240 mg twice daily.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved a new, twice-daily oral medication, dimethyl fumarate, for relapsing-remitting multiple sclerosis.

The drug, to be marketed as Tecfidera, is thought to defend the brain against oxidative stress, and experimental evidence has suggested that it may also act both as an anti-inflammatory and as a neuroprotective agent.

Tecfidera joins a host of already approved medications for MS. Two forms of interferon beta-1a (Avonex and Rebif) and two forms of interferon beta-1b (Betaseron and Extavia) have been approved for the relapsing-remitting form, as has glatiramer acetate (Copaxone), fingolimod (Gilenya), and teriflunomide (Aubagio). Natalizumab (Tysabri) is approved for relapsing-remitting MS, but with restrictions. Mitoxantrone (Novantrone) is approved for secondary progressive, progressive-relapsing, and worsening relapsing-remitting MS, according to the National MS Society. Dalfampridine (Ampyra) is approved to improve walking in individuals with MS.

"No drug provides a cure for multiple sclerosis, so it is important to have a variety of treatment options available for patients," said Dr. Russell Katz, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.

According to the FDA, MS is among the most common causes of neurologic disability in young adults and occurs more frequently in women than men. Some 400,000 Americans are living with the condition, and the relapsing-remitting form is the most common. That is characterized by episodes of worsening function, followed by recovery periods. But recovery periods become less complete over time, leading to progressive decline in function and increased disability.

Dimethyl fumarate was approved based on results from two phase III trials that enrolled more than 2,600 patients: DEFINE and CONFIRM. DEFINE data were originally reported at the Fourth Cooperative Meeting on Multiple Sclerosis in 2011 and the CONFIRM data were reported at the Joint Congress of ECTRIMS/ACTRIMS in 2012.

According to Biogen Idec, which makes dimethyl fumarate, relapses were reduced by 49% in patients taking the drug in the DEFINE trial, and disability by 38%. Relapses declined by 34% in the CONFIRM study. In both trials, dimethyl fumarate significantly reduced lesions in the brain, when compared with placebo.

"In clinical trials, patients treated with dimethyl fumarate had less disease activity when compared to patients on placebo – whether they were in the early stages of MS or had more established disease," said Dr. Robert Fox, medical director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic, in a Biogen statement. Dr. Fox was the lead investigator of the CONFIRM study, and is a paid adviser for Biogen Idec for projects not related to dimethyl fumarate. "This drug provides physicians with an important additional treatment option for their patients across the MS spectrum," Dr. Fox said.

The FDA said that dimethyl fumarate decreases lymphocyte counts, but that there was no evidence of an increase in infections in patients taking the drug in trials. The agency recommends monitoring lymphocyte counts before starting therapy, and annually thereafter. Flushing and gastrointestinal problems were the most common adverse reactions.

Biogen said the drug would be available in a matter of days. The recommended starting dose is 120 mg twice a day orally. After a week, the recommended dose increases to 240 mg twice daily.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved a new, twice-daily oral medication, dimethyl fumarate, for relapsing-remitting multiple sclerosis.

The drug, to be marketed as Tecfidera, is thought to defend the brain against oxidative stress, and experimental evidence has suggested that it may also act both as an anti-inflammatory and as a neuroprotective agent.

Tecfidera joins a host of already approved medications for MS. Two forms of interferon beta-1a (Avonex and Rebif) and two forms of interferon beta-1b (Betaseron and Extavia) have been approved for the relapsing-remitting form, as has glatiramer acetate (Copaxone), fingolimod (Gilenya), and teriflunomide (Aubagio). Natalizumab (Tysabri) is approved for relapsing-remitting MS, but with restrictions. Mitoxantrone (Novantrone) is approved for secondary progressive, progressive-relapsing, and worsening relapsing-remitting MS, according to the National MS Society. Dalfampridine (Ampyra) is approved to improve walking in individuals with MS.

"No drug provides a cure for multiple sclerosis, so it is important to have a variety of treatment options available for patients," said Dr. Russell Katz, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.

According to the FDA, MS is among the most common causes of neurologic disability in young adults and occurs more frequently in women than men. Some 400,000 Americans are living with the condition, and the relapsing-remitting form is the most common. That is characterized by episodes of worsening function, followed by recovery periods. But recovery periods become less complete over time, leading to progressive decline in function and increased disability.

Dimethyl fumarate was approved based on results from two phase III trials that enrolled more than 2,600 patients: DEFINE and CONFIRM. DEFINE data were originally reported at the Fourth Cooperative Meeting on Multiple Sclerosis in 2011 and the CONFIRM data were reported at the Joint Congress of ECTRIMS/ACTRIMS in 2012.

According to Biogen Idec, which makes dimethyl fumarate, relapses were reduced by 49% in patients taking the drug in the DEFINE trial, and disability by 38%. Relapses declined by 34% in the CONFIRM study. In both trials, dimethyl fumarate significantly reduced lesions in the brain, when compared with placebo.

"In clinical trials, patients treated with dimethyl fumarate had less disease activity when compared to patients on placebo – whether they were in the early stages of MS or had more established disease," said Dr. Robert Fox, medical director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic, in a Biogen statement. Dr. Fox was the lead investigator of the CONFIRM study, and is a paid adviser for Biogen Idec for projects not related to dimethyl fumarate. "This drug provides physicians with an important additional treatment option for their patients across the MS spectrum," Dr. Fox said.

The FDA said that dimethyl fumarate decreases lymphocyte counts, but that there was no evidence of an increase in infections in patients taking the drug in trials. The agency recommends monitoring lymphocyte counts before starting therapy, and annually thereafter. Flushing and gastrointestinal problems were the most common adverse reactions.

Biogen said the drug would be available in a matter of days. The recommended starting dose is 120 mg twice a day orally. After a week, the recommended dose increases to 240 mg twice daily.

aault@frontlinemedcom.com

On Twitter @aliciaault

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Percutaneous transluminal venous angioplasty – also known as "liberation therapy" – doesn’t help people with multiple sclerosis and may increase MS brain activity in the short term, according to a small, randomized, sham-controlled trial from the State University of New York at Buffalo, the first randomized trial to investigate the procedure.

It "was ineffective in correcting" chronic cerebrospinal venous insufficiency (CCSVI), the recently described condition it targets. "The results ... caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials," the investigators concluded.

The findings follow a recent Food and Drug Administration warning that PTVA (percutaneous transluminal venous angioplasty) can cause deaths and injuries, including strokes, damage to the treated vein, blood clots, cranial nerve damage, abdominal bleeding, and detachment and migration of stents.

The idea is to use balloon angioplasty and stents to widen veins in the chests and necks that appear to be narrowed in some MS patients. Proponents of the procedure say that those narrowed veins impair blood flow and lead to disease progression. The researchers who discovered the problem dubbed it CCSVI. A cottage industry has since sprung up to offer PTVA to MS patients.

The FDA noted in its warning that there have been no "controlled ... rigorously conducted, properly targeted" studies of the issue; that may have changed when Dr. Robert Zivadinov, a professor in the department of neurology at SUNY-Buffalo, presented his team’s findings at the annual meeting of the American Academy of Neurology.

"When you reopened those veins in the neck, I think something happened in reperfusing the brain and re-exacerbating disease activity. The message of this is clear. The majority of patients who are relapsing-remitting should not undergo this treatment," he said in an interview.

Ten patients got PTVA in the first phase of the study. The second phase randomized 9 to PTVA and 10 to a sham intervention. Most had relapsing-remitting MS.

There were no MS relapses in the first phase, but PTVA patients had more relapses (4 vs. 1; P = .389) and more MRI disease activity (cumulative number of new contrast-enhancing lesions (19 vs. 3; P = .062) and new T2 lesions (17 vs. 3; P = .066) in the 6 months following treatment in phase II.

PTVA patients also didn’t fare any better on Expanded Disability Status Scale (EDSS) scores, Multiple Sclerosis Functional Composite scores, 6-minute walk tests, or measures of cognition and quality of life.

"We chose very active patients who had one relapse in the previous year or [gadolinium-] enhancing lesions in the 3 months before. The sample size is small, but [more than half] of patients in the treatment group showed increased activity," Dr. Zivadinov said.

The majority of the subjects were women. On average, they were about 45 years old, had been diagnosed with MS for 11 years, and were mildly to moderately disabled (mean EDSS score about 4). Most were on interferon, glatiramer acetate, or both.

Venous angioplasty didn’t cause any serious complications, and it restored venous outflow to at least 50% of normal in most patients. Phase I patients had a better than 75% improvement overall. Phase II patients had less benefit; there were no differences in venous hemodynamic insufficiency scores between treated and sham patients.

The treatment "failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes," and "more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

The work was funded primarily by SUNY-Buffalo’s Neuroimaging Analysis Center and Baird MS Research Center. Dr. Zivadinov receives personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco Imaging, and Questcor Pharmaceuticals.

aotto@frontlinemedcom.com

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.

There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.

"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.

"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.

So far, daclizumab appears to be particularly good at slowing MS progression.

"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.

That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.

In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).

The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.

Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.

The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).

"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.

He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.

There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.

The skin problems "present on their own because the patients report them," he noted.

The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com

SAN DIEGO – It seems okay to switch patients with relapsing-remitting multiple sclerosis to 40-mg glatiramer acetate injections three times a week if the usual 20-mg daily injections get to be too much, according to Dr. Omar Khan, interim chair of the neurology department at Wayne State University in Detroit.

"Our patients love what the molecule does" for them, but some want to quit if the daily shots cause too much lipoatrophy or too many injection-site reactions. "I tell them rather than going off it, go every other day. [That] alternative is okay," he said in an interview.

The assertion is based in part on the randomized, blinded GALA (Glatiramer Acetate Low Frequency Administration Study), which Dr. Khan led and presented at the annual meeting of the American Academy of Neurology.

The trial randomized 943 relapsing-remitting multiple sclerosis patients to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections.

After a year, the placebo patients had an annualized relapse rate of 0.505, compared with a rate of 0.331 for the glatiramer acetate (GA) patients, a 34.4% reduction (P less than .0001). Similarly, the cumulative number of new or enlarging T2 lesions was 34.7% lower in the GA group, and the cumulative number of enhancing T1 lesions was 44.8% lower (P less than .0001 for both).

Although the trial did not pit 20 mg daily against 40 mg three times a week, Dr. Khan noted that the cumulative weekly dose is similar in both regimens, and that the response seen in the 40-mg group was comparable to what would be expected with 20 mg daily.

Injection-site redness, itching, and pain were more common in the GA group, as were headaches; 8.9% of the GA patients and 6.7% of the placebo patients left the study. Those results are also consistent with 20-mg daily injections.

There were no significant baseline differences between the groups. About 70% of the patients were women, they were about 38 years old on average, and almost all were white. The mean baseline Expanded Disability Status Scale score was about 2.7 in both arms, and patients were about 8 years out from diagnosis. The GA group had a baseline T2 lesion load of 19.7 mL, while the placebo group a baseline load of 17.4 mL.

It had been at least 2 years since any of the subjects had monoclonal antibodies, at least 6 months since they had used systemic corticosteroids, and at least 2 months since using immunomodulators. All the patients were GA naïve. The majority were from eastern Europe.

"We have a small phase II immunologic study," Dr. Khan noted, that pitted 20 mg daily against 40 mg every other day. "There were a lot of advantages of taking it every other day" – fewer injection-site reactions and the like – and "immunologically there was no difference" between the two regimens, he said. The study hasn’t been published yet.

In general, "if you look at just your general clinical observations, you can’t tell" which regimen patients are using, he said.

There’s debate about whether it’s better to start patients on a daily regimen, or if it’s okay to go with less frequent injections right out of the gate.

"You might generate a better Th2 [T-cell] shift if you keep them on every day for a few months, and then alter them. It could be true. The fact is that that sample in a large cohort does not exist. [Either way,] it doesn’t change a whole lot because at 6 months [and] 12 months everybody is doing well," Dr. Khan said.

In the meantime, "many of our patients routinely take [GA] less than every other day. They skip weekends; they create their own regimens," he said.

Teva Pharmaceuticals, the maker of GA, paid for the study. Dr. Khan has received personal compensation and research support from Teva, Biogen-Idec, and other companies.

aotto@frontlinemedcom.com

SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.

Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.

Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.

At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.

Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.

As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.

SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.

Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.

Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.

At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.

Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.

As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.

SAN DIEGO—Early detection of progressive multifocal leukoencephalopathy (PML) may reduce mortality and disability levels in patients with multiple sclerosis (MS), according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The research could have implications for patients with MS who receive natalizumab, which increases the risk of PML.

Tuan Dong-Si, MD, Medical Director at Biogen Idec in Weston, Massachusetts, and colleagues examined 319 individuals with MS who were treated with natalizumab and diagnosed with PML. The investigators compared patients who had symptoms of PML at the time of diagnosis with patients who had no symptoms of PML but were diagnosed with the disease by brain scans and spinal fluid tests for John Cunningham virus. Patients' level of disability was assessed before the PML diagnosis, at the time of the diagnosis, six months after the diagnosis, and one year after the diagnosis.

Twenty-one participants had no PML symptoms at the time of their diagnosis, and 298 individuals had symptoms. The study's preliminary data suggest that patients who have no symptoms at diagnosis may have improved survival and less disability than those who had developed symptoms before their diagnosis, according to Dr. Dong-Si.

At the time of PML diagnosis, individuals without symptoms had an average score of 67 on the Karnofsky Performance Scale. In contrast, participants with symptoms had an average score of 54. One year after PML diagnosis, the average Karnofsky score of patients with no symptoms at diagnosis was 70, compared with 47 for patients with symptoms at diagnosis.

Karnofsky scores lower than 50 indicate that the patient may not be able to care for himself or herself and may require institutional care. A Karnofsky score of 70 suggests that the person can care for himself or herself, but may not be able to engage in normal activities or work. A Karnofsky score of 50 indicates that a person may require considerable assistance and frequent medical care.

As of January 1, 2013, all 21 participants with no symptoms at the time of PML diagnosis were alive, compared with 77% of those with symptoms at the time of diagnosis. "These results suggest that the consequences of PML infection can be mitigated by early detection of the disease," said Dr. Dong-Si.

A small group of Republicans and Democrats in the House has introduced federal legislation to limit patients’ out-of-pocket costs for biologics and other specialty medications often used to treat rheumatoid arthritis, psoriasis, lupus, multiple sclerosis, and some cancers.

The Patients’ Access to Treatments Act (H.R. 460), which was introduced on Feb. 4, would require health plans to charge the same copayments for biologics and specialty drugs that they do for other off-formulary brand-name medications.

Typically, health plans use a three-tier system with set copays for generic drugs (tier 1), brand-name drugs (tier 2), and off-formulary brand-name drugs (tier 3). But some insurers have moved biologics and other high-cost medications into a fourth tier, where patients pay a percentage of the cost of the drug. The costs of the affected medications range from $12,000 to $48,000 a year or more, and the copays can range from 25% to 33%, according to the American College of Rheumatology.

"Over the past 2 years, hearing the stories of patients struggling to pay for medications that would dramatically improve their lives has been heartbreaking," Rep. David McKinley (R-W.Va.), the sponsor of the bill, said in a statement. "After talking with a number of people in these situations, it was clear action was needed."

Rep. McKinley introduced this legislation in the last session of Congress, but the bill stalled in committee.

m.schneider@elsevier.com

A small group of Republicans and Democrats in the House has introduced federal legislation to limit patients’ out-of-pocket costs for biologics and other specialty medications often used to treat rheumatoid arthritis, psoriasis, lupus, multiple sclerosis, and some cancers.

The Patients’ Access to Treatments Act (H.R. 460), which was introduced on Feb. 4, would require health plans to charge the same copayments for biologics and specialty drugs that they do for other off-formulary brand-name medications.

Typically, health plans use a three-tier system with set copays for generic drugs (tier 1), brand-name drugs (tier 2), and off-formulary brand-name drugs (tier 3). But some insurers have moved biologics and other high-cost medications into a fourth tier, where patients pay a percentage of the cost of the drug. The costs of the affected medications range from $12,000 to $48,000 a year or more, and the copays can range from 25% to 33%, according to the American College of Rheumatology.

"Over the past 2 years, hearing the stories of patients struggling to pay for medications that would dramatically improve their lives has been heartbreaking," Rep. David McKinley (R-W.Va.), the sponsor of the bill, said in a statement. "After talking with a number of people in these situations, it was clear action was needed."

Rep. McKinley introduced this legislation in the last session of Congress, but the bill stalled in committee.

m.schneider@elsevier.com

A small group of Republicans and Democrats in the House has introduced federal legislation to limit patients’ out-of-pocket costs for biologics and other specialty medications often used to treat rheumatoid arthritis, psoriasis, lupus, multiple sclerosis, and some cancers.

The Patients’ Access to Treatments Act (H.R. 460), which was introduced on Feb. 4, would require health plans to charge the same copayments for biologics and specialty drugs that they do for other off-formulary brand-name medications.

Typically, health plans use a three-tier system with set copays for generic drugs (tier 1), brand-name drugs (tier 2), and off-formulary brand-name drugs (tier 3). But some insurers have moved biologics and other high-cost medications into a fourth tier, where patients pay a percentage of the cost of the drug. The costs of the affected medications range from $12,000 to $48,000 a year or more, and the copays can range from 25% to 33%, according to the American College of Rheumatology.

"Over the past 2 years, hearing the stories of patients struggling to pay for medications that would dramatically improve their lives has been heartbreaking," Rep. David McKinley (R-W.Va.), the sponsor of the bill, said in a statement. "After talking with a number of people in these situations, it was clear action was needed."

Rep. McKinley introduced this legislation in the last session of Congress, but the bill stalled in committee.

m.schneider@elsevier.com

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.

Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.

Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.

“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.

“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.

“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.

“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”

Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

“In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.”

Functional recovery has become possible for some patients following the introduction of disease-modifying therapies with increased efficacy. Oral formulations of fingolimod, dimethyl fumarate, and teriflunomide also could become highly effective treatment options in the coming years. As these and other new drugs emerge, they could expand the number of patients who can achieve remission or improvement—and also make the suppression of MS disease activity increasingly feasible.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.

Ludwig Kappos’s assessment of approved and emerging oral disease-modifying therapies (DMTs) for multiple sclerosis and his comparison of these medicines with injectable therapies nicely summarizes efficacy and safety data for fingolimod, dimethyl fumarate, teriflunomide, and laquinimod.

Although these drugs were primarily compared to placebo in pivotal trials, all were also compared with injectable DMTs. Dimethyl fumarate was compared with glatiramer acetate, fingolimod and laquinimod were compared with intramuscular interferon beta-1a, and teriflunomide was compared with a high dose of subcutaneous interferon beta-1a.

Some clinical and MRI outcomes significantly favored fingolimod over interferon beta 1-a, whereas laquinimod did not demonstrate superiority to the latter drug. Dimethyl fumarate also showed a significant reduction in relapse rate in the 240-mg tid dosage group (but not in the 240-mg bid group) and on some MRI indicators, compared with glatiramer acetate. None of these drugs, however, showed a benefit versus a comparator on disability progression. In most instances, the comparator data did not reflect the primary outcome of the trial.

The best way to compare efficacy is by well-designed, head-to-head trials. Such studies require a large number of patients and are expensive to carry out. Whether such studies will eventually be initiated remains to be seen. Although preliminary evidence from the oral drug pivotal trials suggests the comparative efficacy of each, more studies are clearly needed. It is worth remembering that not all the injectable DMTs have the same effect on MRI or clinical outcomes, which must be considered when comparison studies are carried out.

Lastly, it is still early in the assessment of the relative safety of oral drugs, safety being the other major factor in drug assessment. On the other hand, the interferons and glatiramer acetate have been shown to have excellent safety records over long periods of time.