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Intensive cognitive training may be needed for memory gains in MS
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.
in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.
To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.
Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.
After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.
To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.
Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.
Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.
Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.
“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.
Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.
Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.
REPORTING FROM ECTRIMS 2019
Baseline neurofilament light levels track with brain volume loss in MS
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
STOCKHOLM – according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).
Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.
Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.
Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.
NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.
To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.
Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.
Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.
Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).
Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.
Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.
“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.
Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.
REPORTING FROM ECTRIMS 2019
Tocilizumab beat azathioprine for NMOSD
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
STOCKHOLM – according to data reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
The tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorders (TANGO) trial, explained senior investigator Fu-Dong Shi, MD, PhD, tracked the time to first NMOSD relapse for patients randomized either to tocilizumab or azathioprine. After 60 weeks of participation in the head-to-head trial, 86% of patients receiving tocilizumab remained relapse-free, compared with 56.9% of those on azathioprine. By 90 weeks of therapy, the relapse-free rate held at 86% for those receiving tocilizumab, compared with 48.1% for those on azathioprine, for a 76.4% relative reduction in risk of relapse.
Patients with concomitant autoimmune disease saw particular benefit from tocilizumab compared with azathioprine. On tocilizumab, 78.8% of those with concomitant autoimmune disease remained relapse-free at 90 weeks, a rate that did not differ significantly from that seen in those without other autoimmune disease. However, 22.3% of those with concomitant autoimmune disease who received azathioprine remained relapse-free at 90 weeks, compared with 63.5% of those without autoimmune disease.
Dr. Shi, of the Tianjin (China) Medical University General Hospital, explained that there was limited evidence for the advantage of newer disease-modifying therapies (DMTs) over such older medications as azathioprine to treat NMOSD. Therefore, he said, he and other investigators in the Chinese Medical Network for Neuroinflammation (CMNN), including first author Chao Zhang, MD, initiated a randomized, multicenter, open-label trial that compared tocilizumab to azathioprine for highly relapsing NMOSD.
A total of 118 patients were enrolled. To participate, patients had to meet the 2015 international consensus criteria for NMOSD, and have had at least two relapses in the past year or three relapses within the preceding 2 years.
After a washout period, participants were randomized 1:1 to receive daily oral azathioprine dosed at 2-3 mg/kg or intravenous tocilizumab dosed at 8 mg/kg every 4 weeks. Participants continued on the assigned regimen for at least 60 weeks.
Secondary endpoints included 12-week confirmed disability progression. Here, 35.8% of those on azathioprine saw disability progression, compared with 9.9% on tocilizumab, for a 72.5% relative risk reduction. Serum aquaporin 4-IgG titers fell further for those taking tocilizumab.
In terms of safety, 83% of those on azathioprine and 61% of those receiving tocilizumab had a treatment-related adverse event, as determined by investigator assessment. About half of patients in each group experienced moderate adverse events, and about 90% had mild adverse events in each group. However, there were twice as many severe adverse events among those taking azathioprine. There was one NMOSD-related death in each group.
Subgroup analyses looked at baseline disability scores, number of previous relapses, disease duration, and age at randomization. None of these variables made a difference in the statistically better performance of tocilizumab compared with azathioprine, with hazard ratios ranging from 0.076 to 0.343 in favor of tocilizumab for all subgroups.
Patients were almost all female (92% overall) and about 47 years old at baseline, with a 6-year history of NMOSD.
Overall, 83% of the cohort had experienced optic neuritis over the preceding 2 years, and 94% had experienced acute myelitis. Other manifestations of NMOSD, such as acute brainstem syndrome and symptomatic cerebral syndrome, were much less frequent, occurring in 4%-30% of patients.
Most patients (71%) had been on oral corticosteroids before the washout period, and 34% had been taking mycophenolate mofetil. Azathioprine was taken by 44% of patients at baseline.
Additional data captured during the TANGO trial are being analyzed and will be reported at a later date, said Dr. Shi. These include optical coherence tomography and visual evoked potentials; magnetic resonance imaging of the brain, spinal cord, and optic nerve; and tracking serum B-cell subpopulations. He added that the investigators are continuing long-term, real-world follow-up of the TANGO patient cohort.
Dr. Shi acknowledged that TANGO was limited by the lack of an independent data monitoring committee and the open-label nature of the study.
The study was funded by Tianjin Medical University; Capital Medical University, Beijing; and the National Science Foundation of China. Dr. Shi and coauthors reported no conflicts of interest.
SOURCE: Zhang C et al. ECTRIMS 2019, Abstract 140.
REPORTING FROM ECTRIMS 2019
Even With No Disease Activity, Recurrence Risk Near 50% When Stopping DMTs for MS
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Newer Drugs Provide Superior Disease Activity Control in Pediatric MS
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Continuous Treatment Reduces Risk of Confirmed Disability Progression in MS
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
Continuation of natalizumab treatment reduces risk of MS relapses during pregnancy
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
STOCKHOLM – according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Continuation of treatment is not associated with major fetal risks.
Pregnancy influences the choice of treatment for patients with MS. Not all therapies are compatible with pregnancy; the newer, more effective treatments in particular may pose risks in this regard. “There is a need to accumulate new data on how to manage our highly active patients with MS – in particular, patients who are treated with natalizumab,” said Doriana Landi, MD, PhD, a research fellow at the University of Rome Tor Vergata.
Data suggest that suspension of natalizumab before pregnancy is associated with significant disease worsening. In 2018, Portaccio et al. found that suspending natalizumab treatment before conception is associated with a higher risk of relapses during pregnancy (Neurology. 2018 Mar 6;90[10]:e832-9). Suspending natalizumab treatment at conception, however, reduced the risk of relapse by a factor of three. Other data have suggested that continuing natalizumab treatment until the 30th week of gestation could protect mothers and guarantee fetal safety.
Comparing two cohorts of women with MS
To investigate this question further, Dr. Landi and colleagues investigated a cohort of 29 women with MS who were receiving natalizumab and became pregnant. They compared this cohort’s outcomes with those of the cohort that Portaccio et al. had studied. The investigators categorized participants in both cohorts into three groups according to the time of their last infusion of natalizumab in relation to their last menstrual period. Group 0 had their last infusion before their last menstrual period, group 1 had their last infusion during the first trimester of pregnancy, and group 2 continued treatment after the first trimester. All women restarted natalizumab post partum and had at least 12 months of follow-up after delivery.
Dr. Landi and colleagues calculated the annualized relapse rate during pregnancy and during 12 months post partum for all groups. They also compared the outcomes of newborns between groups.
Prematurity may have influenced rate of hematologic complications
In all, the researchers analyzed 90 completed pregnancies in 86 women with MS. There were no significant demographic differences between groups. The overall population’s mean age was approximately 31 years, and its median Expanded Disability Status Scale (EDSS) score was about 2. The women gave birth to 94 newborns. Mean gestational age was 38.42 weeks, mean birth weight was 2,878.08 mg, and mean length was 48.23 cm.
Group 0 included 31 patients, group 1 included 30 patients, and group 2 included 28 patients. The median interval between the last dose of natalizumab and last menstrual period was 70 days for group 0, 21 days for group 1, and 197 days for group 2. Group 2 received a median of five natalizumab infusions during pregnancy, with a median interval of 80 days between the last prepartum dose and delivery. The median interval between last prepartum dose and the first postpartum dose was 411 days in group 0, 288 in group 1, and 103 in group 2.
Most pregnancies in group 2 were exposed to natalizumab for at least 28 weeks of gestation. Women in group 2 restarted natalizumab treatment significantly earlier, compared with women in the other groups.
Group 0 had a significantly increased ARR during and after pregnancy, compared with the other groups, and group 2 had the lowest ARR during pregnancy. The mean ARR during pregnancy was 1.06 in group 0, 0.49 in group 1, and 0.09 in group 2. The ARR decreased to 0 in pregnancies exposed to natalizumab for more than 90 days. The mean ARR post partum was 0.39 in group 0, 0.23 in group 1, and 0.10 in group 2. Women in group 0 and group 1 had a higher EDSS during pregnancy than before conception.
Newborns’ mean gestational age, birth weight, and length did not differ significantly between groups. Five newborns in group 2, three of whom were premature, had anemia. This outcome is consistent with previous findings, and prematurity may be a confounding factor, said Dr. Landi. The frequency of birth defects was higher in group 2 than in the other groups, but most of them occurred in one twin, said Dr. Landi. The investigators observed malformations in one group 0 newborn (minor), four group 1 newborns (five minor and one major), and four (two minor and four major) group 2 newborns.
In pregnancy during which natalizumab treatment is prolonged until the third trimester, treatment should be restarted after delivery within 2 weeks of the last infusion to avoid potential doubled rebound, said Dr. Landi. Future studies should examine whether extended dosing is as effective as regular dosing. A larger sample size is needed to estimate risks correctly for newborns in exposed pregnancies and counsel patients appropriately.
Dr. Landi reported receiving travel funding from Biogen, Merck Serono, Sanofi-Genzyme, and Teva; honoraria for speaking from Sanofi-Genzyme and Teva; and consultation fees from Merck Serono and Teva. She is an investigator in clinical trials being conducted for Biogen, Merck Serono, Novartis, Roche, and Teva.
SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.
REPORTING FROM ECTRIMS 2019
Even with no disease activity, recurrence risk near 50% when stopping DMTs for MS
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
STOCKHOLM – according to data presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Of 49 patients who had been on DMT for at least 5 years and had shown no evidence of disease activity (NEDA) during that time, 26 continued to have NEDA through at least 5 years of follow-up, explained Tobias Monschein, MD, of the department of neurology at the Medical University of Vienna.
The cohort of patients had all been taking either interferon beta or glatiramer acetate after a first clinical episode leading to an initial diagnosis of MS. Patients all met Barkhof criteria for MS diagnosis on MRI, and all but six patients had oligoclonal bands found on examination of cerebrospinal fluid.
All patients in the cohort thus met criteria for clinically isolated syndrome (CIS) and MS under the 2017 revisions to the McDonald diagnostic criteria. “To our knowledge, this is the first study determining the risk of disease recurrence in a homogenous cohort of patients with CIS,” reported Dr. Monschein and collaborators.
Before stopping DMT, patients had to show at least 5 years of NEDA status; at that point, patients were offered the opportunity to discontinue medication. The decision to stop or continue taking a DMT was left to individual patient choice, Dr. Monschein said in an interview.
The cohort of patients who decided to discontinue DMT was seen yearly; they received a clinical examination that included expanded disability status scale (EDSS) rating. Patients also received an annual MRI.
Age at DMT discontinuation was predictive of remaining disease free, found Dr. Monschein and collaborators. The 26 patients who continued disease free after DMT discontinuation were a mean 29.7 years old, while patients who had disease recurrence were a mean 22.7 years old.
Looking at age as a dichotomous variable, the investigators found that the 16 patients who were 40 years or older when they stopped DMT had an 18.8% risk of MS recurrence, while the 33 patients younger than 40 years at the time of ceasing DMT had a 60.6% risk of recurrence.
Age, in fact, was the only patient, disease, or therapy characteristic that Dr. Monschein and colleagues found predictive of relapse: “Gender, type of DMT, treatment duration, and CIS symptom did not differ significantly between groups,” they reported.
The data “should not encourage patients to generally stop DMTs after a long NEDA period,” they noted.
In the context of shared patient decision-making, though, the data can inform discussion with patients who wish to discontinue DMTS after long disease-free periods, Dr. Monschein said.
“Physicians should encourage younger people to stay on DMTS despite long lasting NEDA status while in patients [older than] 40 years stopping DMTs together with regular clinical and radiological monitoring could be a reasonable option,” he and his colleagues advised.
Dr. Monschein reported no outside sources of funding and no conflicts of interest.
SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.
REPORTING FROM ECTRIMS 2019
Plasma exchange in natalizumab-related PML shows no benefit, possible harm
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
STOCKHOLM – Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
“This is a very important issue for us as neurologists. I think this data suggests that plasma exchange does not seem to confer an advantage to our patients when it comes to mortality and – albeit with caveats – it actually seems to be associated with worsening of the disability level in survivors,” according to Dr. McGuigan, consultant neurologist at St. Vincent’s University Hospital in Dublin and clinical professor at University College Dublin.
Natalizumab is an effective treatment for patients with highly active MS, but its use is limited by the feared complication of PML. Plasma exchange to clear the drug from the patient’s system is a popular and biologically plausible therapy, but its impact on clinical outcomes had not been formally studied until now.
Examining a database of confirmed PML cases
Dr. McGuigan presented a retrospective study of 723 patients with confirmed PML included in the natalizumab pharmacovigilance database run by Biogen, which markets the drug. A total of 85% (616 patients) underwent plasma exchange. The study’s primary outcome was the survival rate 2 years after PML diagnosis in patients who received plasma exchange, compared with those who did not.
Since the viral load of John Cunningham (JC) virus is known to influence outcome in PML, Dr. McGuigan and coinvestigators stratified the primary outcome based on tertiles of baseline viral copy number (VCN). The key study finding was that, across the range of viral loads, plasma exchange was consistently associated with a numerically worse 2-year survival rate, although the difference did not reach statistical significance. Among patients with less than a log5 baseline JC virus VCN, 2-year survival was 88.2% in the plasma exchange group, compared with 89.3% in the patients who did not undergo plasma exchange. For patients with a JC virus VCN greater than log5 but not more than log7, the survival rate was 89.3% without plasma exchange versus 73.8% with the intervention. In the group with greater than a log7 VCN, the 2-year survival was 78.9% without plasma exchange and 68.2% with it.
Statistically significant covariates
In a multivariate Cox proportional hazards analysis, plasma exchange was associated with a statistically nonsignificant 44% increased risk of mortality at 2 years post PML diagnosis. However, several other covariates emerged as statistically significant independent predictors of 2-year mortality. These included age greater than 50 years at diagnosis of PML, with an associated hazard ratio of 1.56, compared with younger patients; male gender (HR, 1.48); a JC virus VCN greater than log 7, compared with log 5 or less (HR, 2.86); a VCN greater than log5 but not more than log7, compared with a VCN of log5 or less (HR, 2.11); and widespread as opposed to localized MRI brain lesions of PML (HR, 1.61). In contrast, an asymptomatic presentation of PML was protective, with an HR of 0.38, compared with patients with a symptomatic presentation.
The likelihood of survival at 2 years was not affected by the number of plasma exchange cycles utilized, the number of natalizumab infusions received prior to diagnosis of PML, or the time from the last natalizumab infusion to starting plasma exchange.
Additional analyses focused on functional ability and disability
A secondary analysis addressed the question of whether plasma exchange has a favorable impact on functional ability. This is an important issue because many MS patients who remain alive 2 years after diagnosis of PML are left with marked permanent disability. This analysis was restricted to the 523 MS patients with PML for whom Expanded Disability Status Scale (EDSS) scores were available 6 months or more after PML diagnosis. The key finding here was that, at 2 years, 62% of the plasma exchange group, but only 38% of non–plasma exchange controls, were either dead or had an EDSS score of 7 or greater, which is a degree of disability likely to render a patient unable to live independently.
Of note, the median EDSS score 6 months before diagnosis of PML was 3.5 in both groups. Moreover, the median EDSS score at the time of diagnosis was similar in the two groups as well: 4.0 in those who underwent plasma exchange and 4.5 in those who did not. So the physician decision to employ plasma exchange clearly was not driven by more-severe disability.
In a multivariate analysis, plasma exchange was independently associated with a 168% increased likelihood of death or an EDSS score of 7 or more at 2 years. A sensitivity analysis restricted to patients who fell into that category was supportive of the main analysis: it concluded that such patients were 159% more likely to have received plasma exchange than not.
Dr. McGuigan cited several study limitations, including possible selection bias, inability to assess the potential impact of other disease-modifying therapies utilized after PML diagnosis, the lack of baseline EDSS scores in a fair number of patients, and the necessity to evaluate all-cause mortality rather than death attributable to PML.
He made a plea for neurologists to diligently submit their own cases of natalizumab-associated PML in MS patients to the Biogen pharmacovigilance database, which is totally dependent upon voluntary physician reporting.
“This is the only tool by which we can get this information at present. It’s the best data we’re likely to be able to get,” he observed.
The study was funded by Biogen. Dr. McGuigan reported receiving research grants from and serving as an advisor to that company and several other pharmaceutical companies.
SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.
REPORTING FROM ECTRIMS 2019
Key clinical point: Plasma exchange has no clinical benefit in natalizumab-associated progressive multifocal leukoencephalopathy (PML).
Major finding: The risk of composite endpoint of death or an Expanded Disability Status Scale of 7.0 or more at follow-up 2 years after a natalizumab-associated PML diagnosis was an adjusted 168% greater in multiple sclerosis patients who underwent plasma exchange than in those who did not.
Study details: A retrospective analysis of the records of 723 multiple sclerosis patients with confirmed natalizumab-associated PML.
Disclosures: The study was funded by Biogen. The presenter reported receiving research grants from and serving as an advisor to Biogen and several other pharmaceutical companies.
Source: McGuigan C et al. ECTRIMS 2019, Abstract 63.
Ofatumumab has superior efficacy in relapsing-remitting MS, compared with teriflunomide
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
STOCKHOLM – (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
Two concurrent phase 3 trials
Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.
The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.
The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
Ofatumumab improved clinical and imaging outcomes
In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.
Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.
Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.
In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.
Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.
REPORTING FROM ECTRIMS 2019