Multiple Sclerosis

Autologous hematopoietic stem cell transplantation was an effective treatment option for aggressive multiple sclerosis, particularly in patients with inflammatory activity at baseline, in a study of the Swedish experience with the procedure since it was first performed there in 2004.

A prospective, observational study of 41 patients with MS treated with autologous hematopoietic stem cell transplantation (HCST) showed a 5-year, relapse-free survival rate of 87% and disease-free survival of 68%. The data also showed a magnetic resonance imaging (MRI) event-free survival rate of 85% and expanded disability status scale (EDSS) score progression-free survival of 77%.

"We know that HSCT causes a profound renewal of the immune system and not just long-lasting immune suppression," wrote first author Dr. Joachim Burman from Uppsala (Sweden) University Hospital and his colleagues. "At least part of the effect is likely related to removal of autoreactive cells, but some of these cells probably escape the treatment and remain after HSCT."

Autologous HSCT has been used to treat MS for nearly two decades and was initially used to treat progressive forms of MS, but when the procedure did not stop deterioration in patients with progressive disease, researchers found that it could be effective in treating highly aggressive relapsing-remitting MS. However, no randomized controlled trial has been performed, few case series have been published, and systematic safety and efficacy follow-up data for relapsing-remitting MS are scarce, the authors noted.

In the study, patients with ongoing inflammatory activity at baseline showed the most significant treatment response, and 79% of these patients had no new MRI lesions, relapses, or EDSS score progression following treatment.

The EDSS score improved in relapsing-remitting patients from a median of 5.5 at the time of HSCT to 3.25 at 1 year and 3 at 2 years, and in those with progressive forms of MS the median score stayed at 6.5 at those three time points.

Of the 41 patients, 34 had relapsing-remitting MS and 7 had other progressive forms of MS. All of the patients had at least 1 year of follow-up, and the mean duration was 47.4 months (J. Neurol. Neurosurg. Psychiatr. 2014 Feb. 19 [doi: 10.1136/jnnp-2013-307207]).

Researchers noted that new disease activity, when it did occur, was predominantly seen during the first 2 years after treatment, and no patient who remained disease-free during the first 3 years – meaning no relapses, no new MRI lesions, and no EDSS progression – went on to have a clinical relapse or develop new MRI lesions.

No deaths were associated with the treatment, although almost all patients experienced acute toxicity during hospitalization. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

The research was supported by the Swedish Association of Persons with Neurological Disabilities, the MÅH Ländell Foundation, and Uppsala University Hospital. The authors declared individual funding, support, and grants from a range of pharmaceutical companies.

Autologous hematopoietic stem cell transplantation was an effective treatment option for aggressive multiple sclerosis, particularly in patients with inflammatory activity at baseline, in a study of the Swedish experience with the procedure since it was first performed there in 2004.

A prospective, observational study of 41 patients with MS treated with autologous hematopoietic stem cell transplantation (HCST) showed a 5-year, relapse-free survival rate of 87% and disease-free survival of 68%. The data also showed a magnetic resonance imaging (MRI) event-free survival rate of 85% and expanded disability status scale (EDSS) score progression-free survival of 77%.

"We know that HSCT causes a profound renewal of the immune system and not just long-lasting immune suppression," wrote first author Dr. Joachim Burman from Uppsala (Sweden) University Hospital and his colleagues. "At least part of the effect is likely related to removal of autoreactive cells, but some of these cells probably escape the treatment and remain after HSCT."

Autologous HSCT has been used to treat MS for nearly two decades and was initially used to treat progressive forms of MS, but when the procedure did not stop deterioration in patients with progressive disease, researchers found that it could be effective in treating highly aggressive relapsing-remitting MS. However, no randomized controlled trial has been performed, few case series have been published, and systematic safety and efficacy follow-up data for relapsing-remitting MS are scarce, the authors noted.

In the study, patients with ongoing inflammatory activity at baseline showed the most significant treatment response, and 79% of these patients had no new MRI lesions, relapses, or EDSS score progression following treatment.

The EDSS score improved in relapsing-remitting patients from a median of 5.5 at the time of HSCT to 3.25 at 1 year and 3 at 2 years, and in those with progressive forms of MS the median score stayed at 6.5 at those three time points.

Of the 41 patients, 34 had relapsing-remitting MS and 7 had other progressive forms of MS. All of the patients had at least 1 year of follow-up, and the mean duration was 47.4 months (J. Neurol. Neurosurg. Psychiatr. 2014 Feb. 19 [doi: 10.1136/jnnp-2013-307207]).

Researchers noted that new disease activity, when it did occur, was predominantly seen during the first 2 years after treatment, and no patient who remained disease-free during the first 3 years – meaning no relapses, no new MRI lesions, and no EDSS progression – went on to have a clinical relapse or develop new MRI lesions.

No deaths were associated with the treatment, although almost all patients experienced acute toxicity during hospitalization. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

The research was supported by the Swedish Association of Persons with Neurological Disabilities, the MÅH Ländell Foundation, and Uppsala University Hospital. The authors declared individual funding, support, and grants from a range of pharmaceutical companies.

Autologous hematopoietic stem cell transplantation was an effective treatment option for aggressive multiple sclerosis, particularly in patients with inflammatory activity at baseline, in a study of the Swedish experience with the procedure since it was first performed there in 2004.

A prospective, observational study of 41 patients with MS treated with autologous hematopoietic stem cell transplantation (HCST) showed a 5-year, relapse-free survival rate of 87% and disease-free survival of 68%. The data also showed a magnetic resonance imaging (MRI) event-free survival rate of 85% and expanded disability status scale (EDSS) score progression-free survival of 77%.

"We know that HSCT causes a profound renewal of the immune system and not just long-lasting immune suppression," wrote first author Dr. Joachim Burman from Uppsala (Sweden) University Hospital and his colleagues. "At least part of the effect is likely related to removal of autoreactive cells, but some of these cells probably escape the treatment and remain after HSCT."

Autologous HSCT has been used to treat MS for nearly two decades and was initially used to treat progressive forms of MS, but when the procedure did not stop deterioration in patients with progressive disease, researchers found that it could be effective in treating highly aggressive relapsing-remitting MS. However, no randomized controlled trial has been performed, few case series have been published, and systematic safety and efficacy follow-up data for relapsing-remitting MS are scarce, the authors noted.

In the study, patients with ongoing inflammatory activity at baseline showed the most significant treatment response, and 79% of these patients had no new MRI lesions, relapses, or EDSS score progression following treatment.

The EDSS score improved in relapsing-remitting patients from a median of 5.5 at the time of HSCT to 3.25 at 1 year and 3 at 2 years, and in those with progressive forms of MS the median score stayed at 6.5 at those three time points.

Of the 41 patients, 34 had relapsing-remitting MS and 7 had other progressive forms of MS. All of the patients had at least 1 year of follow-up, and the mean duration was 47.4 months (J. Neurol. Neurosurg. Psychiatr. 2014 Feb. 19 [doi: 10.1136/jnnp-2013-307207]).

Researchers noted that new disease activity, when it did occur, was predominantly seen during the first 2 years after treatment, and no patient who remained disease-free during the first 3 years – meaning no relapses, no new MRI lesions, and no EDSS progression – went on to have a clinical relapse or develop new MRI lesions.

No deaths were associated with the treatment, although almost all patients experienced acute toxicity during hospitalization. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

The research was supported by the Swedish Association of Persons with Neurological Disabilities, the MÅH Ländell Foundation, and Uppsala University Hospital. The authors declared individual funding, support, and grants from a range of pharmaceutical companies.

The progression of disability in patients with multiple sclerosis was associated with whole brain, cortical, and putamen atrophy during the first 5 years after diagnosis, driven chiefly by a greater decline in gray matter than in white matter volume, according to a report published online in Journal of Neurology, Neurosurgery & Psychiatry.

To identify markers of disability progression in MS, researchers assessed 81 patients residing in Southwestern Norway who were diagnosed in 1998 or 2000 and underwent full neurologic assessments and brain MRI at that time, as well as 5 and 10 years later. Patients whose disability progressed, based on the Expanded Disability Status Scale, during follow-up were no different from those whose disability remained stable in demographic factors, MS subtype, or the use or duration of disease-modifying treatment, said Dr. Cecilie Jacobsen of the department of neurology at Stavanger (Norway) University Hospital and the Neuroimaging Analysis Center at the State University of New York at Buffalo, and her associates.

At 5 years, disease progression was associated with significantly greater volume declines in patients with disease than in those without in measurements of the whole brain (–3.8% vs. –2.0%), cortex (–3.4% vs. –1.8%), and putamen (–10.6% vs. –3.8%). However, at 10 years, there was only a nonsignificant trend toward decreased whole brain volume among patients with disease progression. The correlation was much stronger between disability progression and the decline in gray matter volume than it was between disability progression and the decline in white matter volume. "These findings strengthen the increasing evidence that [gray matter] pathology may be playing a crucial role in MS-related disability progression," the investigators wrote (J. Neurol. Neurosurg. Psychiatry 2014 Feb. 19 [doi:10.1136/jnnp-2013-306906]).

They cautioned that their study was limited by its relatively small sample size and by its "considerable" dropout rate (38%) through 10 years.

Dr. Jacobsen’s associates reported ties to numerous industry sources.

cnnews@frontlinemedcom.com

The progression of disability in patients with multiple sclerosis was associated with whole brain, cortical, and putamen atrophy during the first 5 years after diagnosis, driven chiefly by a greater decline in gray matter than in white matter volume, according to a report published online in Journal of Neurology, Neurosurgery & Psychiatry.

To identify markers of disability progression in MS, researchers assessed 81 patients residing in Southwestern Norway who were diagnosed in 1998 or 2000 and underwent full neurologic assessments and brain MRI at that time, as well as 5 and 10 years later. Patients whose disability progressed, based on the Expanded Disability Status Scale, during follow-up were no different from those whose disability remained stable in demographic factors, MS subtype, or the use or duration of disease-modifying treatment, said Dr. Cecilie Jacobsen of the department of neurology at Stavanger (Norway) University Hospital and the Neuroimaging Analysis Center at the State University of New York at Buffalo, and her associates.

At 5 years, disease progression was associated with significantly greater volume declines in patients with disease than in those without in measurements of the whole brain (–3.8% vs. –2.0%), cortex (–3.4% vs. –1.8%), and putamen (–10.6% vs. –3.8%). However, at 10 years, there was only a nonsignificant trend toward decreased whole brain volume among patients with disease progression. The correlation was much stronger between disability progression and the decline in gray matter volume than it was between disability progression and the decline in white matter volume. "These findings strengthen the increasing evidence that [gray matter] pathology may be playing a crucial role in MS-related disability progression," the investigators wrote (J. Neurol. Neurosurg. Psychiatry 2014 Feb. 19 [doi:10.1136/jnnp-2013-306906]).

They cautioned that their study was limited by its relatively small sample size and by its "considerable" dropout rate (38%) through 10 years.

Dr. Jacobsen’s associates reported ties to numerous industry sources.

cnnews@frontlinemedcom.com

The progression of disability in patients with multiple sclerosis was associated with whole brain, cortical, and putamen atrophy during the first 5 years after diagnosis, driven chiefly by a greater decline in gray matter than in white matter volume, according to a report published online in Journal of Neurology, Neurosurgery & Psychiatry.

To identify markers of disability progression in MS, researchers assessed 81 patients residing in Southwestern Norway who were diagnosed in 1998 or 2000 and underwent full neurologic assessments and brain MRI at that time, as well as 5 and 10 years later. Patients whose disability progressed, based on the Expanded Disability Status Scale, during follow-up were no different from those whose disability remained stable in demographic factors, MS subtype, or the use or duration of disease-modifying treatment, said Dr. Cecilie Jacobsen of the department of neurology at Stavanger (Norway) University Hospital and the Neuroimaging Analysis Center at the State University of New York at Buffalo, and her associates.

At 5 years, disease progression was associated with significantly greater volume declines in patients with disease than in those without in measurements of the whole brain (–3.8% vs. –2.0%), cortex (–3.4% vs. –1.8%), and putamen (–10.6% vs. –3.8%). However, at 10 years, there was only a nonsignificant trend toward decreased whole brain volume among patients with disease progression. The correlation was much stronger between disability progression and the decline in gray matter volume than it was between disability progression and the decline in white matter volume. "These findings strengthen the increasing evidence that [gray matter] pathology may be playing a crucial role in MS-related disability progression," the investigators wrote (J. Neurol. Neurosurg. Psychiatry 2014 Feb. 19 [doi:10.1136/jnnp-2013-306906]).

They cautioned that their study was limited by its relatively small sample size and by its "considerable" dropout rate (38%) through 10 years.

Dr. Jacobsen’s associates reported ties to numerous industry sources.

cnnews@frontlinemedcom.com

Antibodies to the potassium channel KIR4.1 have been discovered in a cohort of people who later developed multiple sclerosis, and not in healthy controls, suggesting that anti-KIR4.1 antibodies may play a role in disease pathogenesis.

In an abstract released Feb. 21 in advance of the annual meeting of the American Academy of Neurology, Dr. Viola Biberacher of Technical University Munich and her colleagues, examined blood samples that had been collected from 16 MS patients between 2 and 9 months before their first clinical attack. The investigators also looked at earlier samples from the same cohort taken up to 6 years before the first attack.

In the cohort, seven patients were positive for anti-KIR4.1 antibodies, two showed borderline activity, and seven were negative. Anti-KIR4.1 antibodies were found in samples taken several years before the first clinical attack, and antibody titers varied at different time points before the first attack; titers before and after disease onset did not differ significantly. None of the 16 age- and sex-matched healthy controls had antibodies to KIR4.1.

Dr. Bernhard Hemmer, also of Technical University Munich and the corresponding author of the study, had been part of the research team that first established KIR4.1 as an immune target in MS. In an observational study of patients with active MS (n = 397), compared with patients with other neurological diseases (n = 329) and healthy blood donors (n = 59), anti-KIR4.1 antibodies were found in almost half (47%) of blood samples from people with MS. No evidence of anti-KIR4 antibodies were found in the healthy controls, and they occurred in less than 1% of people with other neurological diseases (N. Engl. J. Med. 2012;367:115-23).

In the current study as well, about half of the patients who went on to develop MS had antibodies to KIR4.1. The full results of the study will be presented at the meeting in Philadelphia.

In an interview, Dr. Hemmer said that because of the very small sample size of patients in this study, these results must be interpreted with caution. "Replication in independent cohorts is essential," he said.

Dr. Hemmer added that while anti-KIR4.1 antibodies appear to be present in about half of MS patients, "we have not observed a particular phenotype of MS to be associated with these antibodies. However, larger studies are underway to address this issue."

If KIR4.1 is proves to be a relevant immune target in MS, something that will take additional studies to confirm, treatment might involve specific immune therapies that could focus on silencing antibodies to KIR4.1, Dr. Hemmer said. "I could also envision drugs that protect the KIR4.1 channel from damage, or enhance its function if the antibody is disturbed or dysregulated in the MS lesion. But all these therapies require first additional studies to strengthen the hypothesis that the channel plays an important role in MS."

Further studies are looking at expression of KIR4.1 in the brain and MS lesions, and investigating cellular immune responses to KIR4.1.

Currently, no commercial assay is available for KIR4.1, as the protein is difficult to express and purify. "We are working on this too, but it will take time," Dr. Hemmer said.

The KIR4.1 study was funded by the German Ministry for Education and Research and the German Competence Network for Multiple Sclerosis. Dr. Biberacher reported having no conflicts of interest related to the study, but several coauthors hold a patent on KIR4.1 antibody testing in MS. Dr. Hemmer has received past support from Roche, Biogen Idec, Bayer, Novartis, Merck Serono, Metanomics, and Teva.

Antibodies to the potassium channel KIR4.1 have been discovered in a cohort of people who later developed multiple sclerosis, and not in healthy controls, suggesting that anti-KIR4.1 antibodies may play a role in disease pathogenesis.

In an abstract released Feb. 21 in advance of the annual meeting of the American Academy of Neurology, Dr. Viola Biberacher of Technical University Munich and her colleagues, examined blood samples that had been collected from 16 MS patients between 2 and 9 months before their first clinical attack. The investigators also looked at earlier samples from the same cohort taken up to 6 years before the first attack.

In the cohort, seven patients were positive for anti-KIR4.1 antibodies, two showed borderline activity, and seven were negative. Anti-KIR4.1 antibodies were found in samples taken several years before the first clinical attack, and antibody titers varied at different time points before the first attack; titers before and after disease onset did not differ significantly. None of the 16 age- and sex-matched healthy controls had antibodies to KIR4.1.

Dr. Bernhard Hemmer, also of Technical University Munich and the corresponding author of the study, had been part of the research team that first established KIR4.1 as an immune target in MS. In an observational study of patients with active MS (n = 397), compared with patients with other neurological diseases (n = 329) and healthy blood donors (n = 59), anti-KIR4.1 antibodies were found in almost half (47%) of blood samples from people with MS. No evidence of anti-KIR4 antibodies were found in the healthy controls, and they occurred in less than 1% of people with other neurological diseases (N. Engl. J. Med. 2012;367:115-23).

In the current study as well, about half of the patients who went on to develop MS had antibodies to KIR4.1. The full results of the study will be presented at the meeting in Philadelphia.

In an interview, Dr. Hemmer said that because of the very small sample size of patients in this study, these results must be interpreted with caution. "Replication in independent cohorts is essential," he said.

Dr. Hemmer added that while anti-KIR4.1 antibodies appear to be present in about half of MS patients, "we have not observed a particular phenotype of MS to be associated with these antibodies. However, larger studies are underway to address this issue."

If KIR4.1 is proves to be a relevant immune target in MS, something that will take additional studies to confirm, treatment might involve specific immune therapies that could focus on silencing antibodies to KIR4.1, Dr. Hemmer said. "I could also envision drugs that protect the KIR4.1 channel from damage, or enhance its function if the antibody is disturbed or dysregulated in the MS lesion. But all these therapies require first additional studies to strengthen the hypothesis that the channel plays an important role in MS."

Further studies are looking at expression of KIR4.1 in the brain and MS lesions, and investigating cellular immune responses to KIR4.1.

Currently, no commercial assay is available for KIR4.1, as the protein is difficult to express and purify. "We are working on this too, but it will take time," Dr. Hemmer said.

The KIR4.1 study was funded by the German Ministry for Education and Research and the German Competence Network for Multiple Sclerosis. Dr. Biberacher reported having no conflicts of interest related to the study, but several coauthors hold a patent on KIR4.1 antibody testing in MS. Dr. Hemmer has received past support from Roche, Biogen Idec, Bayer, Novartis, Merck Serono, Metanomics, and Teva.

Antibodies to the potassium channel KIR4.1 have been discovered in a cohort of people who later developed multiple sclerosis, and not in healthy controls, suggesting that anti-KIR4.1 antibodies may play a role in disease pathogenesis.

In an abstract released Feb. 21 in advance of the annual meeting of the American Academy of Neurology, Dr. Viola Biberacher of Technical University Munich and her colleagues, examined blood samples that had been collected from 16 MS patients between 2 and 9 months before their first clinical attack. The investigators also looked at earlier samples from the same cohort taken up to 6 years before the first attack.

In the cohort, seven patients were positive for anti-KIR4.1 antibodies, two showed borderline activity, and seven were negative. Anti-KIR4.1 antibodies were found in samples taken several years before the first clinical attack, and antibody titers varied at different time points before the first attack; titers before and after disease onset did not differ significantly. None of the 16 age- and sex-matched healthy controls had antibodies to KIR4.1.

Dr. Bernhard Hemmer, also of Technical University Munich and the corresponding author of the study, had been part of the research team that first established KIR4.1 as an immune target in MS. In an observational study of patients with active MS (n = 397), compared with patients with other neurological diseases (n = 329) and healthy blood donors (n = 59), anti-KIR4.1 antibodies were found in almost half (47%) of blood samples from people with MS. No evidence of anti-KIR4 antibodies were found in the healthy controls, and they occurred in less than 1% of people with other neurological diseases (N. Engl. J. Med. 2012;367:115-23).

In the current study as well, about half of the patients who went on to develop MS had antibodies to KIR4.1. The full results of the study will be presented at the meeting in Philadelphia.

In an interview, Dr. Hemmer said that because of the very small sample size of patients in this study, these results must be interpreted with caution. "Replication in independent cohorts is essential," he said.

Dr. Hemmer added that while anti-KIR4.1 antibodies appear to be present in about half of MS patients, "we have not observed a particular phenotype of MS to be associated with these antibodies. However, larger studies are underway to address this issue."

If KIR4.1 is proves to be a relevant immune target in MS, something that will take additional studies to confirm, treatment might involve specific immune therapies that could focus on silencing antibodies to KIR4.1, Dr. Hemmer said. "I could also envision drugs that protect the KIR4.1 channel from damage, or enhance its function if the antibody is disturbed or dysregulated in the MS lesion. But all these therapies require first additional studies to strengthen the hypothesis that the channel plays an important role in MS."

Further studies are looking at expression of KIR4.1 in the brain and MS lesions, and investigating cellular immune responses to KIR4.1.

Currently, no commercial assay is available for KIR4.1, as the protein is difficult to express and purify. "We are working on this too, but it will take time," Dr. Hemmer said.

The KIR4.1 study was funded by the German Ministry for Education and Research and the German Competence Network for Multiple Sclerosis. Dr. Biberacher reported having no conflicts of interest related to the study, but several coauthors hold a patent on KIR4.1 antibody testing in MS. Dr. Hemmer has received past support from Roche, Biogen Idec, Bayer, Novartis, Merck Serono, Metanomics, and Teva.

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.

Sleep disturbances, including obstructive sleep apnea, may be contributing to daytime fatigue in a large proportion of people with multiple sclerosis, based on the results of an observational study of 195 MS patients without additional neurologic disorders, such as Parkinson’s disease or stroke, which could independently increase OSA risk.

Obstructive sleep apnea – a common and treatable disorder – is likely underrecognized in this patient group as aggravating or causing fatigue, according to the investigators, led by Dr. Tiffany J. Braley of the multiple sclerosis center at the University of Michigan, Ann Arbor.

More than half of all subjects, they found, had evidence of an elevated risk for OSA, and a fifth had a prior diagnosis of OSA. OSA risk emerged as a significant predictor of fatigue severity after adjusting for confounding factors.

©toranico/thinkstockphotos.com

In the study, Dr. Braley and her colleagues administered a validated OSA scoring tool called STOP-Bang to all participants to collect information related to snoring, observed apnea, fatigue, blood pressure, body mass index, age, neck circumference, and gender. They also conducted an extensive sleep questionnaire and administrated validated fatigue, insomnia, and sleepiness scoring tools. The researchers consulted patient medical records to assess information on disease severity, depression, and disability (J. Clin. Sleep Med. 2014;10:155-62).

The patients had a mean age of 47 years, and 66% were female. Overall, 41 (21%) had a prior OSA diagnosis, and 110 (56%) had a STOP-Bang score of 3 or greater, which is indicative of elevated OSA risk. A STOP-Bang score of 3 or more functioned as a significant predictor of higher fatigue scores (P = .01). More nocturnal symptoms and higher disability levels also predicted fatigue.

The proportion of subjects at risk of OSA in the study was at the high end of previous estimates in MS patients, Dr. Braley and her colleagues wrote, but they were surprised to find relatively few OSA diagnoses while more than half the cohort had elevated risk, suggesting that the findings may reflect "suboptimal OSA diagnosis patterns."

"Underrecognition of other symptoms that may signal OSA – such as fatigue – may also explain the discrepancy we found, particularly in patients who suffer disproportionately from fatigue because of a comorbid condition (MS)," they wrote.

The investigators noted that the cross-sectional, observational design of their study meant that they could not establish OSA as causing fatigue in the cohort, and acknowledged that sleep disturbance related to other causes could be contributing. In addition, they cautioned, this was a single-site study, and the findings could reflect characteristics of patients referred to the investigators’ clinic.

Nonetheless, they wrote, clinicians caring for patients with MS "should maintain a low threshold" to screen for OSA, and make efforts to identify any nocturnal symptoms that could affect patients’ sleep quality and contribute to daytime fatigue.

The investigators estimated that as much as 40% of fatigue in MS could be eliminated through better diagnosis and successful treatment of patients with OSA.

The study had no outside funding. Dr. Braley and her two coauthors have received research support from companies marketing multiple sclerosis drugs or OSA therapies and in some instances received compensation for activities with such companies. Dr. Braley and coauthors have been named in patents or provisional patents for sleep apnea treatments held by the University of Michigan.

Sleep disturbances, including obstructive sleep apnea, may be contributing to daytime fatigue in a large proportion of people with multiple sclerosis, based on the results of an observational study of 195 MS patients without additional neurologic disorders, such as Parkinson’s disease or stroke, which could independently increase OSA risk.

Obstructive sleep apnea – a common and treatable disorder – is likely underrecognized in this patient group as aggravating or causing fatigue, according to the investigators, led by Dr. Tiffany J. Braley of the multiple sclerosis center at the University of Michigan, Ann Arbor.

More than half of all subjects, they found, had evidence of an elevated risk for OSA, and a fifth had a prior diagnosis of OSA. OSA risk emerged as a significant predictor of fatigue severity after adjusting for confounding factors.

©toranico/thinkstockphotos.com

In the study, Dr. Braley and her colleagues administered a validated OSA scoring tool called STOP-Bang to all participants to collect information related to snoring, observed apnea, fatigue, blood pressure, body mass index, age, neck circumference, and gender. They also conducted an extensive sleep questionnaire and administrated validated fatigue, insomnia, and sleepiness scoring tools. The researchers consulted patient medical records to assess information on disease severity, depression, and disability (J. Clin. Sleep Med. 2014;10:155-62).

The patients had a mean age of 47 years, and 66% were female. Overall, 41 (21%) had a prior OSA diagnosis, and 110 (56%) had a STOP-Bang score of 3 or greater, which is indicative of elevated OSA risk. A STOP-Bang score of 3 or more functioned as a significant predictor of higher fatigue scores (P = .01). More nocturnal symptoms and higher disability levels also predicted fatigue.

The proportion of subjects at risk of OSA in the study was at the high end of previous estimates in MS patients, Dr. Braley and her colleagues wrote, but they were surprised to find relatively few OSA diagnoses while more than half the cohort had elevated risk, suggesting that the findings may reflect "suboptimal OSA diagnosis patterns."

"Underrecognition of other symptoms that may signal OSA – such as fatigue – may also explain the discrepancy we found, particularly in patients who suffer disproportionately from fatigue because of a comorbid condition (MS)," they wrote.

The investigators noted that the cross-sectional, observational design of their study meant that they could not establish OSA as causing fatigue in the cohort, and acknowledged that sleep disturbance related to other causes could be contributing. In addition, they cautioned, this was a single-site study, and the findings could reflect characteristics of patients referred to the investigators’ clinic.

Nonetheless, they wrote, clinicians caring for patients with MS "should maintain a low threshold" to screen for OSA, and make efforts to identify any nocturnal symptoms that could affect patients’ sleep quality and contribute to daytime fatigue.

The investigators estimated that as much as 40% of fatigue in MS could be eliminated through better diagnosis and successful treatment of patients with OSA.

The study had no outside funding. Dr. Braley and her two coauthors have received research support from companies marketing multiple sclerosis drugs or OSA therapies and in some instances received compensation for activities with such companies. Dr. Braley and coauthors have been named in patents or provisional patents for sleep apnea treatments held by the University of Michigan.

Sleep disturbances, including obstructive sleep apnea, may be contributing to daytime fatigue in a large proportion of people with multiple sclerosis, based on the results of an observational study of 195 MS patients without additional neurologic disorders, such as Parkinson’s disease or stroke, which could independently increase OSA risk.

Obstructive sleep apnea – a common and treatable disorder – is likely underrecognized in this patient group as aggravating or causing fatigue, according to the investigators, led by Dr. Tiffany J. Braley of the multiple sclerosis center at the University of Michigan, Ann Arbor.

More than half of all subjects, they found, had evidence of an elevated risk for OSA, and a fifth had a prior diagnosis of OSA. OSA risk emerged as a significant predictor of fatigue severity after adjusting for confounding factors.

©toranico/thinkstockphotos.com

In the study, Dr. Braley and her colleagues administered a validated OSA scoring tool called STOP-Bang to all participants to collect information related to snoring, observed apnea, fatigue, blood pressure, body mass index, age, neck circumference, and gender. They also conducted an extensive sleep questionnaire and administrated validated fatigue, insomnia, and sleepiness scoring tools. The researchers consulted patient medical records to assess information on disease severity, depression, and disability (J. Clin. Sleep Med. 2014;10:155-62).

The patients had a mean age of 47 years, and 66% were female. Overall, 41 (21%) had a prior OSA diagnosis, and 110 (56%) had a STOP-Bang score of 3 or greater, which is indicative of elevated OSA risk. A STOP-Bang score of 3 or more functioned as a significant predictor of higher fatigue scores (P = .01). More nocturnal symptoms and higher disability levels also predicted fatigue.

The proportion of subjects at risk of OSA in the study was at the high end of previous estimates in MS patients, Dr. Braley and her colleagues wrote, but they were surprised to find relatively few OSA diagnoses while more than half the cohort had elevated risk, suggesting that the findings may reflect "suboptimal OSA diagnosis patterns."

"Underrecognition of other symptoms that may signal OSA – such as fatigue – may also explain the discrepancy we found, particularly in patients who suffer disproportionately from fatigue because of a comorbid condition (MS)," they wrote.

The investigators noted that the cross-sectional, observational design of their study meant that they could not establish OSA as causing fatigue in the cohort, and acknowledged that sleep disturbance related to other causes could be contributing. In addition, they cautioned, this was a single-site study, and the findings could reflect characteristics of patients referred to the investigators’ clinic.

Nonetheless, they wrote, clinicians caring for patients with MS "should maintain a low threshold" to screen for OSA, and make efforts to identify any nocturnal symptoms that could affect patients’ sleep quality and contribute to daytime fatigue.

The investigators estimated that as much as 40% of fatigue in MS could be eliminated through better diagnosis and successful treatment of patients with OSA.

The study had no outside funding. Dr. Braley and her two coauthors have received research support from companies marketing multiple sclerosis drugs or OSA therapies and in some instances received compensation for activities with such companies. Dr. Braley and coauthors have been named in patents or provisional patents for sleep apnea treatments held by the University of Michigan.

Multiple sclerosis shows a "striking" association with obesity at age 20 years that strongly interacts with genetic susceptibility, according to an analysis of data from two case-control studies that examined environmental and genetic risk factors for MS.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, said Dr. Anna Karin Hedström of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and her associates.

"The biological explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies," they said.

Three previous studies have suggested that obesity in early life may be linked to increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case-control study and from a separate American case-control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a 7-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their heights and weights had been at age 20 years, from which the investigators calculated body mass index (BMI).

In both studies, participants whose BMI at age 20 years was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5-21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said (Neurology 2014 [doi:10.1212/WNL.0000000000000203]).

Similarly, participants with a slightly lower but still above-normal BMI of 25-27 kg/m² showed a modestly increased risk of developing MS later in life: The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/ m² or greater at age 20 years had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 years had an OR of only 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may raise the risk of HLA-related activation of T cells that attack the CNS.

Both the Swedish and the American study were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of "obese."

This study was supported by several private nonprofit foundations, the Swedish Research Council for Health, Working Life and Welfare, and the U.S. National Institute of Neurological Disorders and Stroke. Dr. Hedström and five of the other seven authors reported no financial conflicts of interest. One coauthor reported ties to numerous industry sources and one reported receiving research support from Swedish government agencies.

Multiple sclerosis shows a "striking" association with obesity at age 20 years that strongly interacts with genetic susceptibility, according to an analysis of data from two case-control studies that examined environmental and genetic risk factors for MS.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, said Dr. Anna Karin Hedström of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and her associates.

"The biological explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies," they said.

Three previous studies have suggested that obesity in early life may be linked to increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case-control study and from a separate American case-control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a 7-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their heights and weights had been at age 20 years, from which the investigators calculated body mass index (BMI).

In both studies, participants whose BMI at age 20 years was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5-21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said (Neurology 2014 [doi:10.1212/WNL.0000000000000203]).

Similarly, participants with a slightly lower but still above-normal BMI of 25-27 kg/m² showed a modestly increased risk of developing MS later in life: The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/ m² or greater at age 20 years had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 years had an OR of only 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may raise the risk of HLA-related activation of T cells that attack the CNS.

Both the Swedish and the American study were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of "obese."

This study was supported by several private nonprofit foundations, the Swedish Research Council for Health, Working Life and Welfare, and the U.S. National Institute of Neurological Disorders and Stroke. Dr. Hedström and five of the other seven authors reported no financial conflicts of interest. One coauthor reported ties to numerous industry sources and one reported receiving research support from Swedish government agencies.

Multiple sclerosis shows a "striking" association with obesity at age 20 years that strongly interacts with genetic susceptibility, according to an analysis of data from two case-control studies that examined environmental and genetic risk factors for MS.

This relationship between adolescent obesity and MS is of the same magnitude as the separate associations between MS and carriage of the high-risk HLA-DRB1*15 allele, absence of the protective HLA-A*02 allele, and smoking, said Dr. Anna Karin Hedström of the Institute of Environmental Medicine, Karolinska Institutet, Stockholm, and her associates.

"The biological explanations for these interactions are far from clear, but the data open [the way] for mechanistically oriented studies," they said.

Three previous studies have suggested that obesity in early life may be linked to increased risk of developing MS later. Dr. Hedström and her colleagues examined this association using data from a Swedish population-based, case-control study and from a separate American case-control study.

In the Swedish study, 1,510 adults with incident MS who were treated at 40 clinics across the country during a 7-year period and 2,017 control subjects completed detailed questionnaires concerning environmental exposures and other factors. The controls were matched for age, sex, and area of residence, and all the participants gave blood samples for HLA typing.

The American study involved 937 white adults with prevalent MS who were members of a single large health maintenance organization covering northern California and 609 white control subjects matched for age, sex, and area of residence. All the participants completed computer-assisted telephone interviews regarding environmental exposures and lifestyle factors.

All the subjects in both studies reported what their heights and weights had been at age 20 years, from which the investigators calculated body mass index (BMI).

In both studies, participants whose BMI at age 20 years was 27 kg/m² or greater showed an increased risk of developing MS later in life, compared with those whose BMI was 18.5-21 kg/m². The odds ratios (ORs) were 2.2 for subjects in the Swedish study and 1.8 for those in the American study, Dr. Hedström and her associates said (Neurology 2014 [doi:10.1212/WNL.0000000000000203]).

Similarly, participants with a slightly lower but still above-normal BMI of 25-27 kg/m² showed a modestly increased risk of developing MS later in life: The ORs were 1.4 in the Swedish study and 1.3 in the American study.

These ORs were unchanged when a sensitivity analysis was performed, including only the study subjects who had been genotyped.

Participants who carried the high-risk HLA-DRB1*15 gene, did not carry the protective HLA-A*02 gene, and had a BMI of 27 kg/ m² or greater at age 20 years had an OR of 16.2 for developing later MS, compared with those who had none of those risk factors. In contrast, subjects who had the same HLA profile but had not been obese at age 20 years had an OR of only 5.1.

The investigators proposed that the low-grade chronic inflammation associated with obesity, together with obesity’s adverse effects on autoimmunity, may raise the risk of HLA-related activation of T cells that attack the CNS.

Both the Swedish and the American study were limited in that they were retrospective and relied on participants’ self-reports. In addition, Dr. Hedström and her associates modified the usual definition of obesity for the purposes of their study. The typical standard for obesity is a BMI of greater than 30 kg/m², not greater than 27 kg/m². However, the number of subjects at this level of BMI was too small in the Swedish cohort to allow accurate analysis, so the researchers combined the top two categories of BMI into one designation of "obese."

This study was supported by several private nonprofit foundations, the Swedish Research Council for Health, Working Life and Welfare, and the U.S. National Institute of Neurological Disorders and Stroke. Dr. Hedström and five of the other seven authors reported no financial conflicts of interest. One coauthor reported ties to numerous industry sources and one reported receiving research support from Swedish government agencies.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

Teriflunomide significantly reduced the annualized relapse rate in patients with relapsing-remitting multiple sclerosis by more than one-third, compared with placebo, in the second of two large, randomized, phase III trials that have been conducted with the drug.

The latest study, called TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis), demonstrated that the 14-mg dose of teriflunomide produced a 36% relative risk reduction in the annualized relapse rate, compared with placebo (P = .0001). A 7-mg dose of the oral MS agent yielded a 22% relative risk reduction (P = .0183).

Teriflunomide 14 mg, but not 7 mg, was also associated with a significantly lower sustained disability accumulation than placebo.

"These data support the use of teriflunomide as an initial therapy for patients with relapsing-remitting multiple sclerosis and as an option for patients who are unable to tolerate other disease-modifying therapies," wrote the TOWER Trial Group investigators (Lancet Neurol. 2014 Jan. 23 [doi: 10.1016/S1474-4422(13)70308-9]).

First author Dr. Christian Confavreux of University Claude Bernard Lyon 1, France, and his associates commented that the findings add to those previously reported from the phase III TEMSO trial (N. Engl. J. Med. 2011;365:1293-303), which showed that teriflunomide 7 mg and 14 mg both reduced the annualized relapse rate by around 31% when compared with placebo. They are also supported by the results of a phase II extension study.

Teriflunomide was approved for the treatment of adults with relapsing-remitting MS in the United States (trade name Aubagio) in 2012 and in Europe in 2013. The drug is the principal active metabolite in leflunomide, which is licensed for the treatment of rheumatoid arthritis.

The TOWER trial involved a total of 1,169 patients with relapsing-remitting MS who were randomized to treatment: 408 were assigned to teriflunomide 14 mg, 372 to teriflunomide 7 mg, and 389 to placebo. The mean age of patients at study entry was approximately 38 years, with just over 80% being of white, 15% of Asian, and 2% of black ethnicity.

The annualized relapse rates were 0.50 for patients treated with placebo, 0.32 for patients treated with teriflunomide 14 mg, and 0.39 for those treated with teriflunomide 7 mg. Absolute risk reductions for teriflunomide 14 mg and 7 mg versus placebo were –0.11 and –0.18, respectively.

A key secondary endpoint was sustained accumulation of disability. This was defined as an increase of at least 1 point on the Expanded Disability Status Scale (EDSS) from baseline that persisted for at least 12 weeks. The hazard ratios for the time to sustained accumulation of disability were 0.68 (P = .0442) for the 14-mg dose of teriflunomide and 0.95 for the 7-mg dose versus placebo.

"The safety and tolerability profile of teriflunomide, as characterized in this and previous studies, was similar for both the 7-mg and 14-mg doses, including long-term treatment observations," the investigators wrote. The most common side effects seen in patients treated with teriflunomide were hair thinning, headache, and increase in alanine aminotransferase concentrations.

Genzyme, a Sanofi company, sponsored the trial. The investigators disclosed financial relationships with Genzyme as well as other companies that manufacture drugs used to treat MS.

The Food and Drug Administration has approved a new higher-dose subcutaneous injection formulation of glatiramer acetate that is injected three times per week instead of daily, according to the manufacturer, Teva.

The approval, announced Jan. 28, is based on the randomized, blinded, placebo-controlled GALA (Glatiramer Acetate Low Frequency Administration) study, in which 943 relapsing-remitting multiple sclerosis patients were randomized to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections. (Read about the trial’s results in a report out of the 2013 American Academy of Neurology annual meeting).

Teva said that it is shipping the 40-mg dose to distribution outlets immediately and it should be available to patients "within days." The new label information can be found here.

The daily 20-mg/mL subcutaneous injection formulation, approved in 1996, will continue to be available.

jevans@frontlinemedcom.com

The Food and Drug Administration has approved a new higher-dose subcutaneous injection formulation of glatiramer acetate that is injected three times per week instead of daily, according to the manufacturer, Teva.

The approval, announced Jan. 28, is based on the randomized, blinded, placebo-controlled GALA (Glatiramer Acetate Low Frequency Administration) study, in which 943 relapsing-remitting multiple sclerosis patients were randomized to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections. (Read about the trial’s results in a report out of the 2013 American Academy of Neurology annual meeting).

Teva said that it is shipping the 40-mg dose to distribution outlets immediately and it should be available to patients "within days." The new label information can be found here.

The daily 20-mg/mL subcutaneous injection formulation, approved in 1996, will continue to be available.

jevans@frontlinemedcom.com

The Food and Drug Administration has approved a new higher-dose subcutaneous injection formulation of glatiramer acetate that is injected three times per week instead of daily, according to the manufacturer, Teva.

The approval, announced Jan. 28, is based on the randomized, blinded, placebo-controlled GALA (Glatiramer Acetate Low Frequency Administration) study, in which 943 relapsing-remitting multiple sclerosis patients were randomized to 40 mg of subcutaneous glatiramer acetate (Copaxone) three times weekly and 461 patients to matched placebo injections. (Read about the trial’s results in a report out of the 2013 American Academy of Neurology annual meeting).

Teva said that it is shipping the 40-mg dose to distribution outlets immediately and it should be available to patients "within days." The new label information can be found here.

The daily 20-mg/mL subcutaneous injection formulation, approved in 1996, will continue to be available.

jevans@frontlinemedcom.com

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

“The FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects,” according to the Genzyme statement. “The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients.” The FDA also said that one or more “additional active comparator clinical trials of different design and execution” are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it “strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision.”

The FDA’s Concerns
FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November 2013 and in documents provided before the meeting.

The FDA raised concerns about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed that the unblinded studies were likely biased, the majority voted 12–6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams