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No new safety concerns seen in combination treatment with dimethyl fumarate
DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.
In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.
"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."
The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.
No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.
For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.
"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."
Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.
On Twitter @whitneymcknight
DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.
In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.
"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."
The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.
No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.
For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.
"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."
Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.
On Twitter @whitneymcknight
DALLAS – The addition of oral delayed-release dimethyl fumarate to conventional treatments for relapsing-remitting multiple sclerosis had safety and tolerability profiles similar to monotherapy with the drug, according to results from a phase II, open-label study.
In the EXPLORE study, the side effects most often recorded in 104 MS patients with breakthrough disease who were given oral delayed-release dimethyl fumarate (Tecfidera) combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Previous phase III, placebo-controlled studies (DEFINE and CONFIRM) indicated similar adverse event rates for dimethyl fumarate (DMF) as monotherapy.
"Adding Tecfidera to interferon-beta and glatiramer did not significantly increase the side effects of each of those drugs alone," Dr. Jonathan Calkwood said in an interview during a poster session at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"White blood cell count declined, generally starting at about 2 months," said Dr. Calkwood, executive director of the Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology in Golden Valley, Minn. "This mirrored what we saw in the phase III studies, where white blood cell count went down and kind of stayed down."
The lymphocyte count decreased from baseline to week 24 by 22% in the delayed-release DMF plus interferon-beta group, and by 7% in the delayed-release DMF plus glatiramer acetate group. "This was also consistent with the phase III trials, where it goes down and stays down, but not enough to discontinue the medication," he said.
No malignancies were observed, and there were no deaths. There was a transient increase in liver transaminases, primarily in the interferon group, but according to Dr. Calkwood, this did not meet Hy’s law criteria. With the exception of one Clostridium difficile infection, there "was no real signal on infectious disease," he said.
For the study, the investigators enrolled patients aged 18-55 years who met McDonald disease criteria and who had an Expanded Disease Status Scale score of less than 5. At the time of enrollment, patients had been taking the same dose of interferon-beta or glatiramer acetate for at least 12 months and had at least one relapse within the past 12 months or a gadolinium-enhancing lesion within 6 weeks. Patients continued on their prescribed MS therapy for the first 2 months of the study before starting oral delayed-release DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months.
"The study was not really long enough to show differences in efficacy, although MRIs were done monthly as a safety measure," Dr. Calkwood said. However, if the question had been that oral delayed-release DMF would somehow interfere with rather than enhance the platform therapies’ respective ability to protect against breakthrough disease, he said that the imaging performed during the add-on therapy phase of the study showed fewer active lesions than the wash-in monotherapy phase. "It further supported what we thought we already knew."
Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.
On Twitter @whitneymcknight
AT THE CMSC/ACTRIMS annual meeting
Key clinical point: Oral delayed-release DMF added to either interferon-beta or glatiramer acetate had adverse event rates similar to those of delayed-release DMF monotherapy.
Major finding: The most common adverse events observed with oral delayed-release DMF combined with either interferon-beta or glatiramer acetate were mild to moderate flushing (42% and 53%, respectively), diarrhea (32% and 15%), and abdominal pain (21% and 6%).
Data source: A phase II, open-label study (EXPLORE) of 104 adult relapsing-remitting multiple sclerosis patients who’d had 12 months of interferon-beta or glatiramer acetate monotherapy.
Disclosures: Dr. Calkwood disclosed that he has financial relationships with Biogen Idec, maker of Tecfidera, as well as Teva Neuroscience, Bayer HealthCare, and EMD Serono. Biogen Idec sponsored this study.
Low immunogenicity rates support peginterferon in MS
DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.
At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.
Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.
"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.
The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).
During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.
"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.
The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.
The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.
Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.
On Twitter @whitneymcknight
DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.
At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.
Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.
"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.
The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).
During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.
"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.
The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.
The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.
Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.
On Twitter @whitneymcknight
DALLAS – Subcutaneous administration of pegylated interferon every 2 or 4 weeks to patients with relapsing-remitting multiple sclerosis was associated with low rates of immunogenicity in a phase III, double-blind randomized trial.
At year 2 of the ADVANCE trial, persistent treatment-emergent antibodies occurred in 1% of patients who’d received pegylated interferon (PEG-INF) beta-1a (at 125 mcg delivered subcutaneously either every 2 weeks or 4 weeks. Patients given 1 year of placebo, followed by 1 year of dose-frequency–blinded PEG-INF beta-1a, had a similarly low rate.
Modification of a drug by adding polyethylene glycol molecules (pegylation) increases its half-life. It may also reduce the drug’s immunogenicity.
"Pegylated interferon may provide efficacy and safety to what we see with currently available therapies, with the added advantage of lower dosing frequencies per month, which may improve compliance for injectable [therapies], and possibly decrease immunogenicity," said Dr. Scott Newsome, director of the neurology outpatient infusion center at Johns Hopkins Hospital, Baltimore.
The overall incidence of antipeginterferon antibodies during the 2 years of observation was 7% in the total study population of 1,516 patients, with no difference between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).
During the 2-year observation of the blinded dosage, the incidence of binding antibodies was 4% in the group that got PEG-INF beta-1a every 2 weeks and 2% with PEG-INF beta-1a every 4 weeks. Antipeginterferon titers were 2% and 6%, respectively.
"I’d also like to point out that the incidence rate of interferon beta-1a neutralizing antibodies was exceedingly low, less than 1% across the entire study and across both treatment arms," Dr. Newsome said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
"No discernible impact on safety or tolerability was observed in this study," Dr. Newsome said, adding that the rate of adverse events such as injection-site reactions did not differ by antibody status or titer.
The findings strengthen PEG-INF’s profile as another potential interferon treatment for relapsing-remitting multiple sclerosis. In March of this year, the Food and Drug Administration extended its review of the Biogen IDEC product by 3 months; their decision is still forthcoming. If approved, the manufacturer plans to market the drug as Plegridy.
The results of the ADVANCE trial presented earlier this year at the annual meeting of the American Academy of Neurology, indicated that the drug met all primary and secondary efficacy endpoints by the end of year 1, and continued to show a similar efficacy and safety profile in year 2.
Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.
On Twitter @whitneymcknight
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: The development of antibodies against PEG-INF beta-1a was low and had no discernible impact on safety or tolerability.
Major finding: There was no difference in the overall incidence of antipeginterferon antibodies during the 2 years of observation between treatment arms (3% in the placebo arm vs. less than 1% in those given PEG-INF beta-1a every 2 weeks and 2% in those given it every 4 weeks).
Data source: A phase III, double-blind, multicenter clinical trial (ADVANCE) involving 1,516 relapsing-remitting multiple sclerosis patients randomized to 1 year of placebo or subcutaneous PEG-INF beta-1a at 125 mcg either every 2 weeks or every 4 weeks followed by rerandomization of the placebo patients to PEG-INF beta-1a for the second year of treatment.
Disclosures: Dr. Newsome declared he has received funding from Biogen IDEC and Genzyme. Biogen IDEC sponsored this study.
VIDEO: Helping MS patients regain use of their limbs
DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.
Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.
Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.
Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.
Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.
Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.
Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE CMSC/ACTRIMS ANNUAL MEETING
Prospective studies needed to compare MS in African Americans and whites
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
DALLAS – There is a need for prospective, multicenter studies to examine the differences between African Americans and whites with multiple sclerosis and their response to therapy, according to Dr. Omar Khan.
The impact of education, disease awareness, and access to health care as covariates must also be included in future studies, "otherwise, this question will continue to come up, to find out whether these factors do or don’t have a bearing on disease severity and outcomes," said Dr. Khan, professor and chair of neurology at Wayne State University, Detroit, during a presentation at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Another point to consider, especially in regard to trials evaluating response to disease-modifying therapies, is that African Americans continue to be a small proportion of participants in these trials, he said.
Up until recent decades, it was believed that multiple sclerosis didn’t affect African Americans. Even today, some resources, such as the National MS Society's website, try to bust that myth first before delving into other facts about multiple sclerosis.
Nearly 10 years ago, Dr. Bruce Cree and his colleagues presented a study about the clinical characteristics of multiple sclerosis in African Americans, compared with whites, and they showed that African American patients were more likely to have a more aggressive disease course, and a greater likelihood of developing opticospinal MS and transverse myelitis (Neurology 2004;63:2039-45).
The study showed that the median time from onset to diagnosis was 1 year in African Americans, compared with 2 years in whites. Also, the median time from onset to treatment was 4 years in African American patients, compared with 5 years in whites. The former group also had a significantly shorter median time to a Kurtzke Expanded Disability Status Scale (EDSS) score of greater than or equal to 6 and 7, compared with whites.
These findings have been consistently shown in later trials.
In 2004, a group in France showed that the MS course was more aggressive in North African than in European patients (Neurology 2007;68:29-32). Researchers found that the mean age of onset was younger in North Africans, compared with Europeans. They also found that the median times to EDSS scores of 4 and 6 were both significantly shorter in the former group.
"You’re going to see this theme in other studies," said Dr. Khan. "Clearly there wasn’t a delay in diagnosing the disease based on these studies."
Then in 2008, a study in France showed that North African migrants with MS appear to be as responsive as other MS patients are to disease-modifying therapies, although they received the treatment sooner than their white counterparts and had more frequent use of immunosuppressive drugs (Mult. Scler. 2008;14:933-9). The study showed that the mean time to an EDSS score of 6 was 6 years in North Africans, which was almost 10 years sooner than in white patients.
In 2009, in a retrospective study of pediatric-onset MS, Dr. Khan and his colleagues yet again found "a more aggressive disease phenotype among American blacks with adult-onset MS," and called for larger multicenter studies, which Dr. Khan continues to advocate for (Pediatr. Neurol. 2009;40:31-3). The group found an earlier onset of disease to initiation of disease-modifying therapy among African American patients, compared with whites, although the difference didn’t reach statistical significance. The relapse rate was also higher among the former group.
Another study on pediatric-onset MS showed that African American patients may be at higher risk for adverse cognitive impact on language and complex attention (Neurology 2010;75:2097-102).
Dr. Khan also pointed to several studies quantifying central nervous system tissue injury in African Americans with MS.
A 2012 study showed that African Americans had a significantly greater lesion volume, compared with white patients, but the brain volumes weren’t significantly different between the two groups. Researchers concluded that "a higher lesion accumulation, rather than a pronounced brain volume decrease, might explain the early progress to ambulatory assistance of [African Americans] with MS" (PLoS One 2012;7:e43061).
"I don’t think we should be arguing that there is a clear indication that African Americans have greater disability, CNS tissue injury, and possibly suboptimal response to therapy," compared with whites, Dr. Khan said.
Other quantitative studies have suggested differences in the disease biology. "And they provide more credence to these observations, despite the fact that almost all of them have been cross-sectional or retrospective," he said, stressing the need for prospectively designed multicenter studies.
"And I think it’s equally important to keep in mind [that] the impact of education, health awareness, and access to health care as covariates at a bare minimum must be included in these studies," Dr. Khan said.
His group conducted a study in 2012 to find out whether there was a difference between African Americans and whites with MS in terms of level of education, disease awareness, and disease severity, but they didn’t find any statistically significant differences.
Additional study is needed, he said.
Dr. Khan said he had no relevant financial disclosures.
On Twitter @naseemmiller
EXPERT ANALYSIS AT THE CMSC/ACTRIMS ANNUAL MEETING
Copaxone lipoatrophy far more common than reported
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
DALLAS – The risk of lipoatrophy with glatiramer acetate is greater than 60%, according to a review of 73 multiple sclerosis patients at one clinic.
The risk is "substantially higher than previously reported and [is] often the sole factor prompting patients to switch to another MS [disease-modifying therapy]. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant," said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside (Calif.) Medical Clinic.
A total of 46 glatiramer acetate (GA, Copaxone) patients (63%) developed lipoatrophy, an injection-site indentation that can be deep and disfiguring; 35 (76%) of them used an autoinjector. Once noted, the dents didn’t improve during a 3-year observation period, which included photographic documentation and instructions on how to inject the drug every 3 months.
In some patients, lipoatrophy developed within the first 3 months of starting the shots and was noted at multiple injection sites, which prompted the team to suspect that an autoimmune reaction was at work. "Upon GA treatment discontinuation, lipoatrophy remained permanent," he noted.
Lipoatrophy "appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasize [with patients] that this isn’t necessarily going to be remedied with plastic surgery. [However,] if patients were stable, most of them thought that this was a small price to pay to be in remission," Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
GA labeling reports the risk of lipoatrophy to be 2% with the 20-mg/mL daily formulation, which has been on the market for almost 2 decades, and 0.5% with the 40-mg/mL three times weekly option, which was approved by the Food and Drug Administration in 2014. Lipoatrophy "is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection," according to the GA label, which is in contrast with the Riverside finding that site rotation wasn’t much help.
Most of the patients at the clinic were women, in keeping with MS epidemiology, and 40 (55%) opted for the autoinjector, specifically the Autoject 2; the device’s labeling notes that the autoinjector can "help with hard-to-reach areas on your body." Perhaps, by helping patients reach those difficult areas, the autoinjector makes it easier to miss the proper subcutaneous fat layer. That might have something to do with the problem, Dr. Bailey said, but the team simply reported their observations and didn’t report any statistical analysis of the findings, so it’s impossible to discern causes, he noted.
The findings aren’t new for some. The "prevalence of lipoatrophy [is] much higher than expected," one team noted several years ago (Can. J. Neurol. Sci. 2004;31:58-63).
No one knows why GA seems to cause lipoatrophy. Maybe "an elevation in tumor necrosis factor–alpha ... causes a dedifferentiation of adipocytes in [subcutaneous] tissue," Dr. Bailey said.
He is a paid spokesman for Genzyme, Biogen, and Teva, the maker of GA. There was no outside funding for the project.
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
autoimmune problem, vigilant injection-site rotation, Dr. Ronald Bailey, glatiramer acetate, GA, Copaxone, lipoatrophy, injection-site indentation, autoinjector, Lipoatrophy, Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Food and Drug Administration, proper injection technique,
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: The rate of lipoatrophy with glatiramer acetate may be much higher than reported in the drug’s label.
Major finding: Of 73 glatiramer acetate patients, 46 (63%) developed lipoatrophy, sometimes within 3 months of starting the shots.
Data Source: Patient observation every 3 months for 3 years.
Disclosures: The lead investigator is a paid spokesman for Teva, the maker of Copaxone. There was no outside funding for the project.
When switching from natalizumab to teriflunomide, timing is key
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
DALLAS – Teriflunomide could be a safe and effective option when patients with multiple sclerosis need to be switched from natalizumab, especially when the oral treatment starts 1 month after the last natalizumab treatment, according to a small, retrospective study.
Multiple studies have shown that natalizumab (Tysabri) is a risk factor for progressive multifocal leukoencephalopathy (PML). "So, there’s always the question of when do we switch," said Dr. Francisco J. Gomez, coauthor of the study and a physician at the MS Center of Northeastern New York in Latham.
"If you don’t switch people [from natalizumab] earlier in the disease, you might end up giving them worsened outcomes," Dr. Gomez said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
At the same time, he noted, "you’re limited on how to switch. So you’re caught between a rock and a hard place. You want to switch them, but you don’t want to lose the only opportunity you have in controlling their disease."
Dr. Gomez and his colleagues looked at the safety and efficacy of teriflunomide (Aubagio), which was approved by theFood and Drug Administration in 2012 and has been shown to cut the annual MS relapse rate by more than a third.
The investigators used the center’s database to conduct a 12-month retrospective study of 30 patients who switched to teriflunomide after receiving natalizumab for more than a year and were all clinically stable. Most patients began the new treatment within 4 weeks of their last natalizumab treatment.
Cranial MRI and a clinical exam were conducted at the time of last natalizumab, and at 3 and 6 months after natalizumab treatment, to check for possible PML and new MS activity.
Of the 30 patients, 11 were triple positive for PML, meaning that they had received more than 24 natalizumab treatments, had prior immunosuppression, and were positive for anti–John Cunningham virus antibody. Fifteen were positive for anti-JCV antibody, and four were negative for anti-JCV antibody.
The mean number of natalizumab treatments was 38, ranging from 14 to 81. The patients’ mean age was 50 years, and 80% were female. Their mean duration of treatment with teriflunomide after natalizumab discontinuation was 13 months, ranging from 6 to 13.
Of all patients, 23 are still on teriflunomide, Dr. Gomez said. None have developed PML. Two have moved away and were lost to follow-up.
Five patients discontinued the treatment, one of whom developed significant exacerbation, including severe optic neuritis 4 weeks after starting on teriflunomide. That patient also had a 3-month delay between last natalizumab dose and the initiation of teriflunomide, compared with the rest, who started within a month of the last natalizumab treatment.
So, "a reduced washout period after natalizumab may be important to lessen breakthrough disease," Dr. Gomez and his colleagues said in the poster presented at the meeting.
Two others discontinued treatment because of persistent diarrhea and abdominal cramps, and one patient withdrew due to hair thinning. Minor diarrhea and transient hair thinning occurred in seven and five patients, respectively.
Despite the clinical exacerbations, "MRI scans haven’t shown disease, so we feel" that the disease is under control, Dr. Gomez said.
He advised physicians "to make the switch as soon as possible, no more than 4 weeks from the last natalizumab infusion, and then monitor the patient closely for potential MS relapse and PML for the next 6 months. Also, we have only been looking at patients switching to teriflunomide who have been stable while on natalizumab. If the patient has had exacerbations while on natalizumab, we usually go to rituximab and perhaps, in the future, alemtuzumab."
Dr. Gomez reported having no disclosures.
On Twitter @naseemmiller
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: Make the switch as soon as possible – no more than 4 weeks from the last natalizumab infusion – and then monitor the patient closely.
Major finding: Despite clinical exacerbations in five patients, MRI scans remained stable.
Data source: A 12-month retrospective study involving 30 patients who switched to teriflunomide after receiving natalizumab for more than a year.
Disclosures: Dr. Gomez reported having no disclosures.
Aquatic therapy deemed beneficial for MS patients
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
DALLAS – Aquatic exercise can be beneficial for individuals with multiple sclerosis, and it can be considered as an adjunct to other therapies, according to a systematic review and a small randomized, controlled trial presented by the same group at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
In the systematic review, all 11 studies had positive outcomes in patients with multiple sclerosis (MS), and none identified any exacerbation or adverse changes in neurologic status, reported Yasser Salem, Ph.D., of the University of North Texas Health Science Center’s Physical Therapy Program, Fort Worth.
Dr. Salem and his colleagues also conducted a single-blind randomized, controlled trial of 20 patients and found better overall scores in all outcome measures in individuals with MS who received aquatic therapy, compared with those who didn’t.
Aquatic therapy has started receiving attention in recent years and is "now recommended by many physicians, therapists, and the National Multiple Sclerosis Society [NMSS] as an adjunct treatment for individuals with multiple sclerosis," Dr. Salem said in an interview.
The therapy uses the unique aspects and natural properties of water and is generally a well-tolerated form of exercise, Dr. Salem said. "There is no specific contraindication to aquatic therapy other than general contraindications associated with exercise and immersion in water such as fever and severe cardiac diseases," he said.
For their systematic review, Dr. Salem and his colleagues analyzed 11 studies that totaled 141 participants with MS. They said this is the first time such a systematic review has been done.
Of the 11 studies, 3 were randomized, controlled trials; 5 had a single-subject design; and 3 were case studies. The length of treatment ranged from 5 to 12 weeks, and the frequency ranged from 1 to 3 times per week. Most studies didn’t report the duration of the workout sessions, but the longest duration was 1 hour. The exercises included stretching, strength training, aerobics, endurance, balance, and general exercises.
All studies indicated that individuals with MS benefited from aquatic therapy, including increases in mobility and muscle strength, improved quality of life, cardiovascular fitness, and grip strength.
"There is a need for more studies with longer-term follow-up to determine if any gains are retained" on a long-term basis, Dr. Salem and his associates wrote in their unpublished study, which was presented as a poster.
Their single-blind randomized, controlled trial included 20 people with chronic MS, and examined the effects of a 10-week aquatic training program on mobility function, strength, fatigue, and quality of life.
Ten participants were in the exercise group and 10 in the control group. The training included strength, balance, walking, and aerobic training, originally designed by the NMSS and implemented at several local community settings sponsored by the local chapter of NMSS, according to the authors.
Participants were assessed 1 week before and after the training by a blinded investigator. Primary outcomes included a self-paced 10-m walk test, timed Up & Go (TUG) test, Berg Balance Scale, grip strength measured by a hand-held dynamometer, Modified Fatigue Impact Scale, Quality of Life using the MS Quality of Life 54 test (MSQOL-54), and a survey and interview.
The average attendance at the training sessions was 78%. No MS-related exacerbations were reported. "Participants reported better overall scores in all outcome measures, compared with participants in the control group," the authors wrote in the poster. The majority were also extremely satisfied with the program.
Currently, there’s not enough evidence to show whether aquatic therapy is superior to land therapy or whether it can substitute for land therapy. But Dr. Salem said that based on the current literature, it can be an adjunct to other forms of therapy. "When properly performed, aquatic therapy is a gentle and invigorating exercise with little or no adverse effects," he said.
Dr. Salem highly recommends the American Physical Therapy Association’s (APTA’s) Aquatic Physical Therapy Section website, aquaticpt.org, and its "Find an Aquatic PT Clinic" feature to search for places that offer aquatic therapy in your state.
In addition, some local support groups offer free aquatic classes for people with MS. For example, some local offices of the NMSS sponsor aquatic exercise programs designed for individuals with MS. An MS Navigator, available at 1-800-344-4867, can be used to find out if other resources are available in your area.
Dr. Salem reported having no financial disclosures.
On Twitter @naseemmiller
AT THE CMSC/ACTRIMS ANNUAL MEETING
Key clinical point: An aquatic exercise regimen may benefit many areas of life for patients with MS without adverse effects.
Major finding: In a review, 11 studies showed positive results for MS patients who received aquatic therapy. A small randomized, controlled trial also showed benefits.
Data source: Systematic review of 11 studies and a single-blind randomized, controlled study of 20 patients.
Disclosures: Dr. Salem reported having no financial disclosures.
MS experts battle over alemtuzumab’s value
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
DALLAS – Should clinicians favor safety or efficacy when choosing whether to use the controversial drug alemtuzumab to treat patients with relapsing-remitting multiple sclerosis?
This was the question at the heart of an impassioned debate during a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
Safety is ‘relative’
"Safety is a relative thing," session panel member Dr. Olaf Stüve told the standing-room-only, and occasionally obstreperous, crowd.
"I think what we’re all struggling with is, ‘What is a good ratio between efficacy and safety that benefits patients more than it hurts them?’" said Dr. Stüve of the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. "I would argue strongly that alemtuzumab has a very good efficacy profile that really outweighs potential safety issues."
Dr. Stüve, who is also chief of the neurology section of Veterans Affairs North Texas Health Care Systems, Dallas, added that because natalizumab (Tysabri) is the current first-line therapy for patients with refractory disease and has its own safety issues, "for that reason alone, we need another player for patients who don’t respond to disease-modifying therapies."
Off-label, off market, ... for now
Until late 2012, clinicians in the United States had been off-label prescribing alemtuzumab, a monoclonal antibody that binds to antigen CD52 that was originally approved and marketed as Campath, a treatment for chronic lymphocytic leukemia. In order to submit the drug to the Food and Drug Administration (FDA) for approval under the name Lemtrada with a specific MS indication, Genzyme pulled alemtuzumab from the U.S. market. Many in the MS community expected the drug to be approved with an MS indication, based on how well it had performed as an off-label treatment.
Alemtuzumab is approved in Europe, Canada, and Australia for use in MS patients. Currently, the only first-line therapy for refractory MS that is available in the United States is natalizumab, although among its drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham (JC) virus antibody.
To the surprise and outrage of many, including the MS Coalition, the FDA rejected Genzyme’s bid to market Lemtrada late last year, citing the lack of double blinding in the CARE MS I and II trials (Comparison of Alemtuzumab and Rebif Efficacy) and concerns over safety.
"It would have been possible to design a double-blinded trial," Dr. Stüve said in an interview. "However, [nearly all] patients are aware which intervention they are receiving based on any flulike symptoms. Similarly, an incidence of 90%-99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent."
Dr. Stüve also said he believed that because the relapse rate was "fairly consistent in the phase II and phase III programs," there was a reduced risk that outcomes were "substantially affected by the trial design."
Genzyme was largely expected to appeal the decision, but instead recently resubmitted its request for approval of Lemtrada, based on additional data and supplemental analyses, including results presented at this year’s American Academy of Neurology annual meeting. In a company statement, Genzyme said it expects FDA action in the fourth quarter of this year.
Lethal ‘poison’
"Alemtuzumab is more poison than good," panel member Dr. Mitchell T. Wallin told the audience at the CMSC/ACTRIMS meeting. An associate professor of neurology at Georgetown University in Washington, and a neurologist at the Veterans Affairs Medical Center, also in Washington, Dr. Wallin said, "My vote is to not approve it."
"I think there is some question about how well this drug actually controls disability progression," said Dr. Wallin, referring to the disparate findings of the CARE MS I and II studies – the former trial failed to show a change in the progression of the expanded disability status scale (EDSS) scores, while the latter trial did.
Data from the CARE studies, FDA reviews, and data presented late last year by Genzyme to the FDA during an advisory panel meeting indicated "there are good efficacy data in terms of MRI and relapse rates, so that impacts the efficacy equation," Dr. Wallin said during the discussion. When asked in an interview about the extended CARE MS trial data, he said, "These data seem to show the stabilization of the MRI out to 3 years."
"There are often lethal consequences to this drug," Dr. Wallin told the audience. Citing data from the alemtuzumab trials, Dr. Wallin said there was a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), which in one case resulted in death.
Approximately 1% of those studied also had dangerously low platelet counts, putting them at high risk for bleeding complications, he said. Opportunistic infections, kidney failure, fetal complications, and even suicidal ideation were all reported adverse events that soured Dr. Wallin’s view of alemtuzumab as a front-runner for first-line therapy. "You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that."
Why be ‘squeamish’?
This long-lasting effect is precisely what Dr. Stüve said makes alemtuzumab an imperative treatment. "This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy," he said. And because the CARE MS extension data indicated that 20% of patients who’d received alemtuzumab received sequential disease-modifying therapy (DMT) with no increase in adverse events, "it shows that alemtuzumab could potentially be used as a very effective induction therapy, up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns. I think this is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease."
Although Dr. Stüve did cite his concerns about ITP, opportunistic infections associated with alemtuzumab, and the occurrence of various malignancies, particularly thyroid kinds, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to possibly anticipate and monitor these conditions and subsequently treat them.
When Dr. Stüve was challenged by panel moderator Dr. Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, Portland, he responded that when viewed within the entire current treatment landscape, the risks of alemtuzumab were worth the benefits. "The other player is natalizumab, which has a 1 in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP," which he said was, like thyroid disease, treatable.
"We should not withhold these kinds of drugs from patients who really need them," he concluded.
The ‘1 percent’
When asked in an interview whether Americans would benefit from seeking treatment with alemtuzumab out of the country, Dr. Bourdette rejected the idea.
"In my opinion, most patients with MS should not be treated with alemtuzumab, so I see very little need for anyone to go out of the country to receive it." And if they did, he warned, they would need extensive follow-up treatment for "autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer."
"I personally consider this to be a very toxic drug that should be used with great caution and in a very small group of patients with very active and difficult-to-control disease, perhaps 1% to 2% of cases at most," he said.
Dr. Stüve said he had no relevant disclosures. Dr. Wallin declared that he has done research for Biogen Idec. Dr. Bourdette declared that he had no relevant disclosures.
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM THE CMSC/ACTRIMS ANNUAL MEETING
VIDEO: Vitamin D helps with optic neuritis, too
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Sufficient vitamin D levels – serum 25-hydroxyvitamin D concentrations greater than 80 nmol/L – appeared to protect against edema of the retinal nerve fiber layer in a prospective cohort study of patients with acute optic neuritis.
An adequate vitamin D level also protected against thinning of the retinal nerve fiber layer (RNFL) ganglion cell layer and other poor outcomes after 6 months in the study of 49 patients (some of whom had multiple sclerosis), according to researchers at the University of Calgary (Alta.).
The team correlated vitamin D levels with optical coherence tomography findings. Vitamin D is known to have anti-inflammatory effects, so it’s the chronic benefit that was surprising, lead investigator Dr. Jodie Burton explained at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
It’s just one more reason that it’s a good idea to check vitamin D levels, and supplement them if necessary, Dr. Burton said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE CMSC/ACTRIMS ANNUAL MEETING
VIDEO: What’s known so far about plasma exchange in MS, neuromyelitis optica
DALLAS – Plasma exchange, or PLEX, is a type of therapeutic apheresis that has been shown to be effective for acute attacks of demyelinating disease, but it’s not to be used for treatment of chronic or progressive multiple sclerosis.
Dr. Brian G. Weinshenker, professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minn., summarized the current evidence and indications for plasma exchange in individuals with multiple sclerosis or neuromyelitis optica and shared a few practice tips at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For the latest guidelines, visit the American Academy of Neurology and the American Society for Apheresis.
nmiller@frontlinemedcom.com On Twitter @naseemsmiller
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Plasma exchange, or PLEX, is a type of therapeutic apheresis that has been shown to be effective for acute attacks of demyelinating disease, but it’s not to be used for treatment of chronic or progressive multiple sclerosis.
Dr. Brian G. Weinshenker, professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minn., summarized the current evidence and indications for plasma exchange in individuals with multiple sclerosis or neuromyelitis optica and shared a few practice tips at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For the latest guidelines, visit the American Academy of Neurology and the American Society for Apheresis.
nmiller@frontlinemedcom.com On Twitter @naseemsmiller
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
DALLAS – Plasma exchange, or PLEX, is a type of therapeutic apheresis that has been shown to be effective for acute attacks of demyelinating disease, but it’s not to be used for treatment of chronic or progressive multiple sclerosis.
Dr. Brian G. Weinshenker, professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minn., summarized the current evidence and indications for plasma exchange in individuals with multiple sclerosis or neuromyelitis optica and shared a few practice tips at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
For the latest guidelines, visit the American Academy of Neurology and the American Society for Apheresis.
nmiller@frontlinemedcom.com On Twitter @naseemsmiller
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE CMSC/ACTRIMS ANNUAL MEETING
