ICYMI Multiple Sclerosis

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

NEW ORLEANS—Laquinimod, an oral, CNS-active therapy for multiple sclerosis (MS), significantly slows disability progression and brain atrophy, compared with placebo, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. The drug’s safety profile suggests that “it may have an important role in the long-term management of MS,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine in Aurora.

Laquinimod reduced the probability of three-month sustained disability by 34% with a hazard ratio of 0.658 and a highly significant P value. “From an exploratory standpoint, if you extend this definition to a six-month sustained disability progression, you get an even larger effect of 46%, again with a significant P value and a hazard ratio of 0.54,” said Dr. Vollmer.

After 24 months, laquinimod reduced the rate of cerebral atrophy by 30%, compared with placebo. “This effect was actually visible at month 12 and was already statistically significant,” observed Dr. Vollmer.

“This effect on disability seems somewhat out of proportion to what we would expect, based on the reduction of the inflammatory phase of the disease,” he continued. After 24 months, patients on laquinimod had a 21% lower annualized relapse rate than patients on placebo. At months 12 and 24, the researchers observed a 30% reduction in the number of gadolinium-enhancing lesions and a 24% reduction in new T2 lesions. These three results were highly statistically significant, but their effects were “modest,” said Dr. Vollmer.

Pooled Analyses of Two Trials
Dr. Vollmer and his colleagues performed pooled analyses of data from the Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon b-1a (BRAVO) phase III trials to assess the effect of laquinimod on relapse, disability, and brain atrophy in patients with MS. The ALLEGRO trial was a randomized, double-blinded, placebo-controlled study comparing 0.6 mg of laquinimod to placebo in patients with relapsing MS. The BRAVO trial was a randomized study that compared the same dose of laquinimod and placebo, but included an open-label comparator arm that was analyzed using a rater-blinded method. The two trials had similar study designs and shared the same primary outcome, secondary outcome, and exploratory end point.

The two patient data sets included almost 2,000 patients, approximately 50% of whom were randomized to laquinimod. About 21% of patients in the placebo arm ultimately were excluded from analysis, and 19% of patients in the laquinimod arm were excluded from analysis, mostly because of withdrawal of consent or failure to reconsent. Approximately 6.4% of the laquinimod group withdrew because of adverse events (primarily gastrointestinal side effects and abdominal pain), compared with 4.7% of the placebo group. About 80% of patients in both groups completed the protocol.

Trials Show Laquinimod’sPositive Safety Profile
Laquinimod was well tolerated among patients in the ALLEGRO and BRAVO trials. Approximately 9% of laquinimod and placebo patients reported experiencing serious adverse events. Six patients receiving laquinimod experienced appendicitis, the most commonly reported serious adverse event, compared with one patient on placebo. Three patients on laquinimod experienced malignant breast neoplasms, compared with one patient on placebo.

Overall, nearly 82% of patients receiving laquinimod experienced adverse events, compared with 76% of patients receiving placebo. Compared with control patients, those receiving laquinimod experienced higher rates of headache (15.1% vs 18.2%), back pain (8.2% vs 13.6%), arthralgia (6.0% vs 7.2%), increased liver enzymes (2.7% vs 5.9%), urinary tract infection (4.2% vs 5.7%), cough (3.1% vs 5.2%), and abdominal pain (2.6% vs 5.0%).

“Laquinimod’s toxicity-related liver function was very mild—0.7% of patients on laquinimod had elevated liver transaminase, compared with 0.4% of placebo,” Dr. Vollmer noted. “In all cases, they were mild elevations and resolved despite patients staying on therapy,” he added.  

To read the accompanying article, please click here.

To read the accompanying article, please click here.

To read the accompanying article, please click here.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Among treatment-naïve patients with relapsing–remitting multiple sclerosis (MS), alemtuzumab reduced the relapse rate by 55%, compared with interferon beta-1a, said Alasdair Coles, PhD, member of the Department of Clinical Neurosciences at Cambridge University in the United Kingdom, at the 64th Annual Meeting of the American Academy of Neurology. Eight percent of patients receiving alemtuzumab experienced sustained accumulation of disability, compared with 11% of patients receiving Rebif, but this difference was not statistically significant, according to findings from the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) study.

“Perhaps most significantly,” the study provided evidence for alemtuzumab’s superiority “on reducing the rate of tissue loss, as measured by MRI, compared to the active drug Rebif,” said Dr. Coles. Alemtuzumab also had a superior effect on measures of neurologic impairment and on MRI measures of new inflammatory lesions, compared with that of Rebif.

In the two-year phase III trial, Dr. Coles and his colleagues randomized 581 treatment-naïve patients from 98 centers in 16 countries to alemtuzumab or interferon beta-1a to compare the clinical efficacy and safety outcomes of the two drugs. All patients had highly active relapsing–remitting MS but had not yet accumulated disability. Participants’ mean age was 33, and their mean Expanded Disability Status Scale (EDSS) score was 2. EDSS raters were blinded to treatment, and all relapses were adjudicated by an independent end point panel.

The annualized relapse rate was 0.18 for patients receiving alemtuzumab, compared with 0.39 for patients receiving interferon beta-1a. Approximately 78% of patients receiving alemtuzumab were relapse-free, compared with nearly 59% of patients receiving interferon beta-1a.

Alemtuzumab was associated with more adverse events than was interferon beta-1a, including infusion-associated symptoms such as headache, pyrexia, and rash. Premedication and further treatment with antihistamines and antipyretics ameliorated these symptoms.

“As we have come to expect, there was an excess of thyroid autoimmunities following alemtuzumab,” said Dr. Coles. In addition, three cases of idiopathic thrombocytopenic purpura occurred in the alemtuzumab arm, and one case occurred in the interferon beta-1a arm. The study’s risk-minimization program identified all cases, and appropriate treatment restored patients’ platelet counts and prevented sequelae.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

NEW ORLEANS—Compared with interferon beta-1a, alemtuzumab reduced the annualized relapse rate by 49% among patients with relapsing–remitting multiple sclerosis (MS) who had relapsed on previous therapy, according to research presented at the 64th Annual Meeting of the American Academy of Neurology. Approximately 65% of patients taking alemtuzumab were relapse-free, compared with 47% of patients taking interferon beta-1a, per results from the phase III Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) study.

In addition, patients with relapsing–remitting MS taking alemtuzumab had a 12.7% risk of sustained accumulation of disability, while patients taking interferon had a 21% risk, said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center. This reduction represents a hazard ratio of 0.58, or 42% treatment effect, he noted.

During a two-year period, the average Expanded Disability Status Scale (EDSS) score decreased by 0.17 steps among patients taking alemtuzumab, compared with an increase of 0.24 steps among patients taking interferon. The net difference of 0.41 EDSS steps between the two groups after two years was statistically significant, said Dr. Cohen, as were the differences between each group’s scores at baseline and at 12 months.

Patients receiving alemtuzumab also experienced a 29% chance of sustained reduction of disability. Patients receiving interferon, in contrast, experienced a 13% chance of this outcome.

Comparing the Same Drugs in a New Patient Population
The results of the study were consistent with those of a previous phase III trial—Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (see sidebar). The two-year CARE-MS II trial, conducted by Dr. Cohen and colleagues, compared the effects of alemtuzumab and interferon beta-1a in patients who had relapsed on prior therapy. The study’s two primary efficacy end points were relapse rate and time to six-month sustained accumulation of disability. Additional end points included EDSS change from baseline and sustained reduction of disability, MRI lesion analyses, and normalized whole-brain volume, as measured by brain parenchymal fraction.

Eligible patients ages 18 to 55 were randomized to receive either 12 mg of alemtuzumab for five days at month 0 and for three days at month 12, or 44 µg of subcutaneous interferon beta-1a three times per week. To prevent side effects, the alemtuzumab patients received three days of IV methylprednisolone with each infusion course, and the same therapy was administered annually to the interferon patients. “Because of the distinct mode of administration and side-effect profiles, we felt that blinding of participants and treating clinicians was not feasible,” said Dr. Cohen.

The patients’ average EDSS score was 2.7, and participants had had an average of 1.5 relapses in the previous year. Approximately 80% of patients had previously received interferon therapy, 30% had received glatiramer acetate, and 20% had received both therapies.

Alemtuzumab Reduces the Number of T2 Lesions
Approximately 46% of patients receiving alemtuzumab had new or enlarging T2 lesions over two years, compared with 68% of patients receiving interferon. Although T2 lesion volume decreased in both patient groups, the difference was not statistically significant. Patients taking alemtuzumab experienced 23% less brain volume loss over two years, as measured by brain parenchymal fraction, compared with patients taking interferon beta-1a.

The overall incidence of adverse events was similar in both groups, as was the incidence of serious adverse events. Infections such as nasopharyngitis, sinusitis, and upper respiratory infection were somewhat more common among patients receiving alemtuzumab, as were serious infections such as pneumonia, appendicitis, and herpes zoster.

“This study showed superior efficacy of alemtuzumab, compared with interferon beta-1a, across multiple outcomes,” said Dr. Cohen. “This is now the third study demonstrating superior efficacy of alemtuzumab, and it’s important to note [that] all three of those studies were against an active comparator—subcutaneous interferon beta-1a—which itself is effective against relapses, disability, and MRI. The adverse event profile was consistent with [that of] previous studies, and a comprehensive monitoring program was successful in early detection, facilitating early treatment,” he concluded.

To hear an audiocast related to this news article, please click here.

To read a commentary on this news article, please click here.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.

Multiple sclerosis (MS) treatments have been available for more than a decade. Several disease-modifying therapies are approved and routinely used with various degrees of effectiveness, tolerability, and compliance. Treatment options have continued to evolve in effectiveness, frequency of administration, and routes of delivery, but more targeted, effective, and safe options are still needed.

The alemtuzumab clinical trial outcome data are exciting. Alemtuzumab represents another effective therapeutic option that will help MS clinicians treat their patients more effectively. This novel agent has demonstrated significant improvement in effectiveness not only for reduced relapse rates and MRI disease activity suppression, but also for reduction of accumulated disability. These impressive and significant gains across multiple outcomes have been accomplished when compared not to placebo, but to one of our mainstays in available treatment. This improved ability to deliver more effective treatment safely and easily, without the worry of ongoing compliance concerns, represents a great advantage in our ongoing fight to limit the damage that this disease causes to our patients, friends, and colleagues.