Multiple Sclerosis

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

[email protected]

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

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.

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.

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.

STOCKHOLM – For women with multiple sclerosis (MS), continuing treatment with natalizumab during pregnancy and post partum is associated with a decreased risk of relapses during pregnancy, compared with washout and early treatment cessation, 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.

[email protected]

SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.

STOCKHOLM – For women with multiple sclerosis (MS), continuing treatment with natalizumab during pregnancy and post partum is associated with a decreased risk of relapses during pregnancy, compared with washout and early treatment cessation, 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.

[email protected]

SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.

STOCKHOLM – For women with multiple sclerosis (MS), continuing treatment with natalizumab during pregnancy and post partum is associated with a decreased risk of relapses during pregnancy, compared with washout and early treatment cessation, 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.

[email protected]

SOURCE: Landi D et al. ECTRIMS 2019, Abstract 338.

STOCKHOLM – Just under half of a small cohort of patients with multiple sclerosis (MS) who discontinued disease modifying therapy (DMT) showed signs of relapse or disease progression on magnetic resonance imaging (MRI). Patients who were younger had a higher probability of relapse, 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.
 

[email protected]

SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.

STOCKHOLM – Just under half of a small cohort of patients with multiple sclerosis (MS) who discontinued disease modifying therapy (DMT) showed signs of relapse or disease progression on magnetic resonance imaging (MRI). Patients who were younger had a higher probability of relapse, 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.
 

[email protected]

SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.

STOCKHOLM – Just under half of a small cohort of patients with multiple sclerosis (MS) who discontinued disease modifying therapy (DMT) showed signs of relapse or disease progression on magnetic resonance imaging (MRI). Patients who were younger had a higher probability of relapse, 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.
 

[email protected]

SOURCE: Monschein T et al. ECTRIMS 2019, Abstract P654.

STOCKHOLM – The largest-ever study of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) demonstrated that plasma exchange is without beneficial effect on clinical outcomes and may well be harmful, Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

“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.

[email protected]

SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.

STOCKHOLM – The largest-ever study of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) demonstrated that plasma exchange is without beneficial effect on clinical outcomes and may well be harmful, Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

“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.

[email protected]

SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.

STOCKHOLM – The largest-ever study of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) demonstrated that plasma exchange is without beneficial effect on clinical outcomes and may well be harmful, Christopher McGuigan, MD, and colleagues reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

“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.

[email protected]

SOURCE: McGuigan C et al. ECTRIMS 2019, Abstract 63.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (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.

[email protected]

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (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.

[email protected]

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (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.

[email protected]

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

[email protected]

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

[email protected]

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

[email protected]

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

[email protected]

SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

[email protected]

SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

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SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.