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BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.
Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The IMSE 1 study with natalizumab
The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).
“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).
Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.
For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.
The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).
JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.
JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.
A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.
Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”
The IMSE 2 study with fingolimod
Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.
Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.
The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.
After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.
Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.
Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
French experience with fingolimod: The VIRGILE study
Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).
Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.
The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.
“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
The IMSE 3 study with alemtuzumab
Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).
In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.
“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.
Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.
“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
The IMSE 5 study with dimethyl fumarate
Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.
The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.
“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.
“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.
Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.
Twelve-year follow-up of teriflunomide shows continued efficacy, safety
Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.
Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.
“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.
For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.
Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.
Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.
Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
Study and author disclosures
The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.
The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.
The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.
BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.
Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The IMSE 1 study with natalizumab
The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).
“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).
Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.
For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.
The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).
JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.
JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.
A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.
Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”
The IMSE 2 study with fingolimod
Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.
Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.
The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.
After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.
Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.
Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
French experience with fingolimod: The VIRGILE study
Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).
Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.
The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.
“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
The IMSE 3 study with alemtuzumab
Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).
In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.
“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.
Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.
“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
The IMSE 5 study with dimethyl fumarate
Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.
The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.
“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.
“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.
Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.
Twelve-year follow-up of teriflunomide shows continued efficacy, safety
Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.
Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.
“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.
For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.
Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.
Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.
Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
Study and author disclosures
The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.
The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.
The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.
BERLIN – Real-world data from six postmarketing surveillance studies suggest that currently available disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have long-lasting effects that are matched by reasonable tolerability.
Long-term efficacy and safety data on natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) from four Swedish studies, one French study, and one international study were reported during a poster session on long-term treatment monitoring at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
The IMSE 1 study with natalizumab
The Immunomodulation and Multiple Sclerosis Epidemiology (IMSE) studies are Swedish postmarketing surveillance studies that were started with the launch of various DMTs in Sweden: natalizumab since 2006 (IMSE 1), fingolimod in 2015 (IMSE 2), alemtuzumab in 2014 (IMSE 3), and dimethyl fumarate in 2014 (IMSE 5).
“Postmarketing surveillance is important for determination of long-term safety and effectiveness in a real-world setting,” Stina Kågström and her associates observed in their poster reporting some findings of the IMSE 1 study with natalizumab (Mult Scler. 2018;24[S2]:699-700, Abstract P1232).
Ms. Kågström of the department of clinical neuroscience at the Karolinska Institute in Stockholm and her colleagues reported that data on 3,108 patients who were seen at 54 Swedish clinics had been collated via the nationwide Swedish Quality Registry for Neurological Care (NEUROreg). NEUROreg started out as an MS register but has since widened its remit to include other neurologic diagnoses.
For the IMSE 1 study, prospectively recorded data regarding natalizumab treatment, adverse events, JC-virus (JCV) status and clinical effectiveness measures were obtained from NEUROreg for 2,225 women and 883 men. Just over one-third (37%, n = 1,150) were still receiving natalizumab at the time of the analysis.
The mean age at which natalizumab was started was 39 years, with treatment primarily given for RRMS (81% of patients) and less often for secondary progressive multiple sclerosis (SPMS, 15%) and rarely for other types of progressive MS. The mean treatment duration was just under 4 years (47.6 months).
JCV testing was introduced in 2011 in Sweden, and this “has led to fewer treated JCV-positive patients,” the IMSE 1 study investigators reported. “This likely explains a reduced incidence of PML [progressive multifocal leukoencephalopathy],” they suggested. There were nine PML cases diagnosed in Sweden from 2008 to the data cut-off point in 2018, one of which was fatal.
JCV status from 2011 onward was available for 1,269 patients, of whom 39% were JCV positive and 61% were JCV negative. The overall drug survival rate was 72% for JCV-negative and 14% for JCV-positive patients. Improved health status was seen, as measured by the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), and the physical and psychological Multiple Sclerosis Impact Scale–29 (MSIS-29) components.
A total of 644 of 1,269 patients discontinued treatment with natalizumab at some point, of whom 67% discontinued because of being JCV positive. The main reason for discontinuation in JCV-negative patients was pregnancy or planning a pregnancy (38%), with lack of effect (10%) and adverse events (11%) as other key reasons for stopping natalizumab.
Ms. Kågström and her associates concluded that natalizumab was “generally well tolerated with sustained effectiveness.”
The IMSE 2 study with fingolimod
Data on the long-term safety and efficacy of fingolimod were reported from the IMSE 2 study (Mult Scler. 2018;24[S2]:696-7, Abstract P1228). Lead author Anna Fält, also of the Karolinska Institute, and her associates analyzed data for 1,634 patients who had been treated with fingolimod from June 2015 to September 2018.
Most patients were older than 30 years (79%), and those aged 30 and older were predominantly female (69%), had an RRMS diagnosis (88%), and been treated for a mean of about 3 years (37 months). A total of 829 were being treated with fingolimod at the time of the analysis, with 844 having discontinued treatment at some point. The main reason for discontinuing treatment with fingolimod was a lack of effect (42% of cases) or an adverse effect (34%). The IMSE 2 study authors reported in their abstract that most patients were switched to rituximab after discontinuing fingolimod.
The number of relapses per 1,000 patient-years was reduced by fingolimod treatment from 280 to 82, comparing before and during treatment for all age groups studied. Relapse rate dropped from 694 per 1,000 patient-years before treatment to 138 during treatment in patients aged 20 years or younger, from 454 to 122 in those aged 21-30 years, and from 257 to 72 in those older than 31 years.
After 1 year of treatment, improvements were seen in the health status of patients as measured by various scales, including the EDSS, MSSS, MSIS-29 Physical, and MSIS-29 Psychological. When the researchers analyzed data by age groups, significant improvements were seen in patients aged 21-30 years and older than 30 years.
Ninety nonserious and 62 serious adverse events were reported in fingolimod-treated patients during the time of analysis. Of the latter, 13 serious adverse events involved cardiac disorders, 12 neoplasms, and 10 infections and infestations.
Overall, the IMSE 2 study investigators said that fingolimod was generally tolerable and reduced disease activity in MS.
French experience with fingolimod: The VIRGILE study
Real-world data on the long-term safety and efficacy of fingolimod in France from the VIRGILE study were reported by Christine Lebrun-Frenay, MD, PhD, and her associates (Mult Scler. 2018;24[S2]:698-9, Abstract P1231).
Dr. Lebrun-Frenay of Pasteur 2 Hospital in Nice and her coauthors noted that VIRGILE study included patients starting treatment with fingolimod between January 2014 and February 2016. A total of 1,047 patients were included, and another 330 patients treated with natalizumab were included at the behest of the French health authorities.
The annualized relapse rate after 2 years of follow-up was 0.30 in the fingolimod group. Dr. Lebrun-Frenay and her colleagues noted: “The 3-year data from this interim analysis provide evidence for sustained efficacy of fingolimod.” Indeed, they report that almost 60% of patients did not relapse and 64% had no worsening of disease. On average, EDSS was stable during the 3-year follow-up period.
“Safety and tolerability profiles of fingolimod were in line with previous clinical experience, with lymphopenia being the most frequent AE [adverse event] reported,” they added.
The IMSE 3 study with alemtuzumab
Long-term experience with alemtuzumab as a treatment for RRMS in the real-world setting is more limited as it only became available for use for this indication in 2014, but some insight is provided by the results of the IMSE 3 study (Mult Scler. 2018;24[S2]:706-7, Abstract P1240).
In total, there were 113 patients treated with alemtuzumab; the vast majority (94%) had RRMS and were aged a mean of 34 years at the start of treatment. Treatment was for more than 12 months in 101 patients, more than 24 months in 86 patients, and more than 36 months in 36 patients.
“In patients treated for at least 12 months, significant improvements were seen in several clinical parameters,” Dr. Fält and her associates observed in their poster at ECTRIMS. The mean baseline and 12-month values for the EDSS were 2.0 and 1.6, and for the MSSS they were 3.46 and 2.61. The mean baseline and 12-month values for the MSIS-29 Psychological subscale were 35.1 and 30.8, respectively, and for MSIS-29 Physical they were 22.7 and 17.7.
Overall, there were 14 nonserious and 11 serious adverse events, the most common of which were infections and infestations, metabolism and nutrition disorders, and immune system disorders.
“A longer follow-up period is needed to assess the real-world effectiveness and safety of alemtuzumab,” the IMSE 3 study authors noted.
The IMSE 5 study with dimethyl fumarate
Similarly, the authors of the IMSE 5 study (Mult Scler. 2018;24[S2]:701-2, Abstract 1234) concluded that a longer follow-up period is need to assess the real-world effectiveness of dimethyl fumarate. Selin Safer Demirbüker, also of the Karolinska Institute, and her associates looked at data on 2,108 patients treated with dimethyl fumarate between March 2014 and April 2018, of whom 1,150 were still receiving treatment at the time of their assessment.
The mean age of patients at the start of treatment was 41 years, 91% had RRMS, and 73% were female. The mean treatment duration was 22.3 months. The majority of patients (n = 867) had been previously treated with interferon and glatiramer acetate (Copaxone) prior to dimethyl fumarate, with 538 being naive to treatment.
“Dimethyl fumarate seems to have a positive effect for patients remaining on treatment,” wrote Ms. Safer Demirbüker and her colleagues. The overall 1-year drug survival reported in their abstract was 74%. Their poster showed a lower 2-year drug survival rate of 63.5% for men and 56.4% for women.
“Swedish patients show cognitive, psychological, and physical benefits after 2 or more years of treatment,” the IMSE 5 study authors further noted. Mean EDSS, MSSS, and MSIS-29 Psychological values all fell from baseline to 2 years.
Overall, 958 (47%) of patients discontinued treatment with dimethyl fumarate at some point, primarily (in 52% of cases) because of adverse events or lack of effect (29% of cases). Most patients (39%) switched to rituximab (15% had no new treatment registered), but 35% of patients continued treatment for 3 or more years.
Twelve-year follow-up of teriflunomide shows continued efficacy, safety
Mark Freedman, MD, of the University of Ottawa and the Ottawa Hospital Research Institute and his associates reported long-term follow-up data on the efficacy and safety of teriflunomide (Aubagio) in relapsing forms of MS (Mult Scler. 2018;24[S2]:700-1, Abstract P1233). After up to 12 years’ follow up, teriflunomide 14 mg was associated with an overall annualized relapse rate of 0.228.
Yearly annualized relapse rates were “low and stable,” Dr. Freedman and his coauthors from the United States, Spain, Italy, France, Germany, England, the Republic of Korea, and Australia noted in their poster.
“As of August 2018, over 93,000 patients were being treated with teriflunomide,” the authors stated. This represented a real-world exposure of approximately 186,000 patient-years up to December 2017, they added.
For the analysis, data from one phase 2 study and three phase 3 studies (TEMSO, TOWER, and TENERE) and their long-term extension studies were pooled. In all, there were 1,696 patients treated with 14 mg of teriflunomide in these studies.
Annualized relapse rates ranged from 0.321 in the first year of follow-up in the studies to 0.080 by the 12th year. The proportions of patients remaining relapse free “were high and stable (ranging from 0.75 in year 1 to 0.93 in years 8 and 9).” EDSS scores were 2.57 at baseline and 2.27 at year 12.
Importantly, no new safety signals were reported, Dr. Freedman and his colleagues wrote, adding that most adverse events were mild to moderate in severity.
Taken together, “these data demonstrate the long-term efficacy and safety of teriflunomide,” they concluded.
Study and author disclosures
The teriflunomide analysis was supported by Sanofi. Dr. Freedman disclosed receiving research or educational grant support from Bayer and Genzyme; honoraria/consulting fees from Bayer, Biogen, EMD Canada, Novartis, Sanofi, and Teva; and membership on company advisory boards/boards of directors/other similar groups for Bayer, Biogen, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, and Teva.
The IMSE 1 and 5 studies were supported by Biogen and the IMSE 2 and 3 studies by Novartis. The lead study authors for the IMSE studies – Dr. Kågström, Dr. Fält, and Dr. Safer Demirbüker – had nothing personal to disclose. Other authors included employees of the sponsoring companies or those who had received research funding or honoraria for consultancy work from the companies.
The VIRGILE study was supported by Novartis Pharma AG, Switzerland. Dr. Lebrun-Frenay disclosed receiving consultancy fees from Merck, Novartis, Biogen, MedDay, Roche, Teva, and Genzyme. Coauthors included Novartis employees.
REPORTING FROM ECTRIMS 2018