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In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues. 
Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.
An Analysis of CARE-MS II Data
Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.
Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.
Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.
Results Consistently Favored Alemtuzumab
In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.
At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.
In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.
At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.
Structural or Functional Repair?
“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”
The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”
Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.
“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.
—Erik Greb
Suggested Reading
Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].
Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].
In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues.
Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.
An Analysis of CARE-MS II Data
Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.
Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.
Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.
Results Consistently Favored Alemtuzumab
In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.
At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.
In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.
At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.
Structural or Functional Repair?
“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”
The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”
Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.
“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.
—Erik Greb
Suggested Reading
Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].
Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].
In addition to slowing disability accumulation, alemtuzumab improves preexisting disability in patients with relapsing-remitting multiple sclerosis (MS) who have had inadequate responses to prior therapies, according to research published online ahead of print October 12 in Neurology. “Disabilities may often be reversible (at least partially) in patients with active relapsing-remitting MS if they receive suitable therapy, irrespective of the type of baseline functional deficit,” said Gavin Giovannoni, MD, PhD, Professor of Neurology at Barts and the London School of Medicine and Dentistry, and colleagues.
Most currently approved therapies for relapsing-remitting MS delay confirmed disability worsening, compared with placebo. The introduction of more potent drugs in recent years, however, has made the goal of confirmed disability improvement (CDI) appear more feasible. In the CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in MS II) trial, CDI was more likely among patients receiving alemtuzumab than among those receiving interferon beta-1a.
An Analysis of CARE-MS II Data
Dr. Giovannoni and colleagues examined prespecified and post hoc disability outcomes of CARE-MS II to characterize alemtuzumab’s effect on preexisting disability. In the trial, patients with relapsing-remitting MS with inadequate response to prior disease-modifying therapies were randomized to alemtuzumab or subcutaneous interferon beta-1a. Patients randomized to alemtuzumab received 12 mg/day of the treatment on five consecutive days at month 0, and on three consecutive days at month 12. Participants randomized to interferon received 44 mg three times weekly. The study lasted for two years.
Blinded raters performed Expanded Disability Status Scale (EDSS) assessments at baseline, every three months, and when relapse was suspected. They administered the MS Functional Composite (MSFC) three times before baseline to attenuate practice effects, and then every six months. Finally, they assessed visual function every six months with the binocular Sloan low-contrast letter acuity (SLCLA) test.
Dr. Giovannoni and colleagues assessed four tertiary end points of CARE-MS II. The first was time to CDI, which was defined as a decrease of one or more points in EDSS from baseline sustained for three or more or six or more months in patients with a baseline score of 2 or greater. The second was the proportion worsened (increase of 0.5 or more points), stable, or improved (decrease of 0.5 or more points) from baseline EDSS. The third was mean change from baseline in MSFC and MSFC plus SLCLA scores and their components. The fourth was proportions worsened (decrease of 0.5 or more standard deviations), stable, or improved (increase of 0.5 or more standard deviations) from baseline MSFC scores.
Results Consistently Favored Alemtuzumab
In all, 202 patients were randomized to interferon beta-1a, and 426 patients were randomized to alemtuzumab. Baseline demographic and clinical characteristics were similar between treatment groups. The groups had comparable percentages of patients with recent prestudy relapse.
At month 24, EDSS improvement, as well as improvement in all seven EDSS functional systems, was more common among patients receiving alemtuzumab, compared with those receiving interferon. Participants receiving alemtuzumab were more than twice as likely as those receiving interferon to have three-month CDI. Among patients with a baseline EDSS of 3 or higher, the proportion of patients with six-month CDI was also significantly greater with alemtuzumab than with interferon. Stratification of results by presence or absence of prior interferon use did not affect the results, nor did stratification by presence or absence of relapse within three months before initiating treatment.
In addition, the likelihood of six-month CDI in MSFC score from baseline to month 24 was greater for patients receiving alemtuzumab than those receiving interferon. Participants in the interferon group were significantly more likely than those in the alemtuzumab group to have 15% or greater worsening in MSFC sustained for six months. The difference between treatment groups in 20% or greater worsening in MSFC sustained for six months was not statistically significant.
At months 12 and 24, visual acuity in patients receiving alemtuzumab was stable at 2.5% contrast and at 100% contrast, but the results were not statistically significant. Participants receiving interferon had a significant decline in visual acuity from baseline to month 12 and from baseline to month 24 at 1.25% contrast and 2.5% contrast. Visual acuity declined significantly from baseline to month 24 in the interferon group at 100% contrast. Differences between treatment groups were significant at 2.5% contrast at months 12 and 24, and at 1.25% contrast at month 12.
Structural or Functional Repair?
“Giovannoni et al demonstrated that comparing two drugs for their efficacy on disability progression omits a crucial aspect of the MS disease process: sustained reduction in disability,” said Bibiana Bielekova, MD, investigator at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and Mar Tintoré, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, in an accompanying editorial. “Comparing both sides of the disability changes [ie, disability progression and disability reduction] between the two drugs doubles the amount of clinically useful information.”
The CARE-MS II design, however, may artificially overestimate the benefit of alemtuzumab over interferon, they added. More than 50% of enrolled patients were previously treated with interferon beta-1a, and the inclusion criteria required the presence of relapses while on this therapy. These factors “technically excluded patients who had optimal therapeutic response to interferon beta-1a,” said Drs. Bielekova and Tintoré. “Nevertheless, a similar observation was seen in treatment-naive patients with relapsing-remitting MS in the CAMMS223 phase II trial.”
Dr. Giovannoni’s group ruled out, to an extent, the possibility that disability improvements resulted solely from the reversal of exacerbation-related disability. Similarly, the observed sustained reduction in disability likely did not simply reflect measurement variance, because the results on various outcomes consistently favored alemtuzumab. “One can only speculate whether the sustained reduction in disability is due to structural repair (ie, remyelination) or functional repair (ie, plasticity, such as formation of new synapses). We favor the latter idea, based on the early experience with CD52-depleting antibody,” said Drs. Bielekova and Tintoré.
“Despite unarguable progress in MS therapeutics, there is still a long road ahead until we can eliminate disease progression for all patients,” they concluded.
—Erik Greb
Suggested Reading
Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Oct 12 [Epub ahead of print].
Bielekova B, Tintore M. Sustained reduction of MS disability: New player in comparing disease-modifying treatments. Neurology. 2016 Oct 12 [Epub ahead of print].