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Ibudilast shows promise in progressive MS
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point: Ibudilast’s positive phase 2 trial results in progressive multiple sclerosis patients bode well for future development.
Major finding: Ibudilast treatment was associated with a 48% slowing in the rate of decline in brain atrophy as measured by brain parenchymal fraction.
Study details: A randomized trial of 255 subjects with progressive MS enrolled at 28 U.S. sites.
Disclosures: The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
Source: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
MS may be a transmissible protein misfolding disorder, study suggests
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
SAN DIEGO – MS may even be caused by prions, potentially putting it into the same category as Creutzfeldt-Jakob disease.
Researchers don’t think MS is contagious between humans. But their findings in mice do suggest that the disease is transmissible from “a seed of protein misfolding,” Shigeki Tsutsui, DVM, PhD, of the University of Calgary (Alta.), said in an interview in advance of his presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“The next question is: ‘What is actually causing primary damage?’ ” he said. “Our hypothesis is that it’s protein misfolding. If protein misfolding targets the central neuron cells, then those damaged cells release a kind of a trigger to start an immune response.”
This isn’t an unusual concept. Protein misfolding is believed to cause several chronic neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, Dr. Tsutsui said.
The researchers focused on the potential transmissibility of human prion protein “since we thought that the prion protein might be the candidate causing the MS,” he said.
Prion diseases are extremely rare and often deadly. They appear when normal cellular prion proteins are induced to misfold when they come in contact with infectious agents known as prions.
In humans, prion diseases include Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru (a condition spread among cannibals who eat the brains of other humans). Most famously, a variant of Creutzfeldt-Jakob disease has been linked – but not conclusively – to the eating of meat from cows infected with mad cow disease.
Depending on the condition, prion diseases can appear spontaneously, via inheritance or through infection.
In the new study, researchers intracerebrally injected brain homogenate from 10 patients with primary or secondary-progressive MS into 36 transgenic mice. All the mice over-expressed human prion protein. A control group of 23 mice were injected with homogenate from six donor brains.
At 6-12 months, the control mice did not develop pathology. However, the mice injected with brain matter from MS patients developed various levels of significant pathology. The researchers also managed to transmit illness from affected mice into another group of transgenic mice that over-expressed human prion protein via injection of brain homogenate.
While the mice in the study represent “a very extreme case” since their levels of prion protein expression were very high, it’s clear that “MS is actually transmissible,” Dr. Tsutsui said.
The study authors speculate that pathogenic prion protein triggers an autoimmune response by degenerating myelin and causing the release of cellular debris.
Could MS also be contagious? It may not be, even if it’s a prion disease, Dr. Tsutsui said. Some prion disease variants are neither contagious nor infectious.
The researchers plan to study the animal model they’ve created and explore the potential for its use in research, Dr. Tsutsui said.
The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
SOURCE: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point: Translational research suggests the primary damage in MS may be caused by transmissible protein misfolding.
Major finding: Transgenic mice over-expressing human prion protein that were injected with brain matter from MS patients developed various levels of significant pathology, and brain homogenate from these mice could transmit illness to naive transgenic mice.
Study details: Transgenic mice over-expressing human prion protein received intracerebral injection of brain homogenate from patients with primary or secondary-progressive MS
Disclosures: The authors have no disclosures with the exception of one who disclosed serving as deputy editor of the Multiple Sclerosis Journal. Funding sources include Canada Research Chairs, Alberta Innovates-Health Solutions, and the Alberta Prion Research Institute.
Source: Tsutsui S et al. ACTRIMS Forum 2018 Abstract LB282.
VIDEO: Could targeting gut dysbiosis in MS prevent disease?
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Compelling findings in a genetically engineered mouse model of multiple sclerosis identify mechanisms of how adolescence and gut dysbiosis contribute to the risk of MS. In addition, disparities in gut microbiome species could explain why some people are at higher risk for developing multiple sclerosis, while others seem to enjoy a protective effect against development of this and other autoimmune diseases.
The hope is that these findings could pave the way for clinicians to potentially prevent development of multiple sclerosis in people at higher risk, perhaps through altering the gut flora and probiotic therapy, Suhayl Dhib-Jalbut, MD, said in a video interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Dr. Dhib-Jalbut and his team discovered these findings using humanized transgenic mice – in other words, mice containing risk genes for triggering disease transferred from a patient with multiple sclerosis. The mice were more likely to develop MS-like disease at certain ages and in the presence of an altered gut microbiome or gut dysbiosis (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
Dr. Dhib-Jalbut is past president of ACTRIMS and is professor and chairman of the departments of neurology at Rutgers–Robert Wood Johnson Medical School, New Brunswick, N.J., and New Jersey Medical School, Newark. He has received research grants from Biogen and Teva, and is a consultant for Genzyme, Teva, Celgene, and, Mallinckrodt.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM ACTRIMS FORUM 2018
Rituximab fails to eliminate meningeal inflammation in progressive MS
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Researchers are heading back to the drawing board after a tiny phase 1 trial of intrathecal rituximab in certain patients with progressive multiple sclerosis failed to eliminate inflammation in the meninges.
The study investigators had hoped the treatment would significantly help progressive MS patients with leptomeningeal inflammation, which has been linked to worsening disease. However, “this paradigm seems to have not gotten rid of the meningeal inflammation significantly. We need a better approach,” said Pavan Bhargava, MD, of Johns Hopkins University, Baltimore, who spoke in an interview in advance of presenting the study findings at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The new study aimed to test the value of targeting immune cell follicles with doses of rituximab given intrathecally – straight into the spinal fluid – to greatly boost the penetration of the drug into the meninges. When given intravenously, Dr. Bhargava said, only a minuscule amount of rituximab makes it to the brain.
Dr. Bhargava’s team screened 36 patients with progressive MS with MRI scans and found that 15 showed signs of meningeal inflammation. Of those, 11 agreed to take part in the study, and 8 fit the criteria.
The participants (median age 55.5 years; five were female) received two intrathecal treatments of 25 mg of rituximab 2 weeks apart, were monitored via follow-up clinical evaluations and lab tests at weeks 2, 8, 24, and 48, and received lumbar punctures and MRI scans at weeks 8 and 24.
“The main outcome was safety,” he said. “Most patients tolerated the rituximab, and the only side effect occurred in one patient who had abnormal sensations in the leg for 35-45 minutes. Otherwise, the medication was safe.”
The researchers detected no change in the meningeal inflammatory lesions before and after the treatment at 24 weeks.
But the tiny dose, much smaller than the typical two doses of 1,000 mg of IV rituximab over 2 weeks, completely depleted B cells in the blood of almost all patients, Dr. Bhargava said. “It was likely leaking out into the blood and clearing the B cells.” Peripheral blood B cells decreased from a median of 18.55% at baseline to 0.1% at week 2 and 8 with an increase to 3.6% at 24 weeks.
This effect was not as robust in spinal fluid, he said, where B cells were not fully depleted.
The findings suggest more cycles of treatment may be needed to target types of immune cells other than B cells, he noted. Or perhaps another drug would work better if it has a different mechanism and can penetrate more effectively.
The next step, he said, is to screen alternative drug approaches in animal models with meningeal inflammation that’s similar to that found in humans.
The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Dr. Bhargava reported no relevant disclosures.
SOURCE: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
FROM ACTRIMS FORUM 2018
Key clinical point:
Major finding: No change in leptomeningeal inflammation was seen after two intrathecal doses of 25 mg of rituximab administered over 2 weeks.
Data source: Prospective study of eight patients with progressive MS and signs of meningeal inflammation.
Disclosures: The study was funded by the International Progressive MS Alliance and the Race to Erase MS. Study presenter Pavan Bhargava, MD, reported no relevant disclosures.
Source: Bhargava P et al. ACTRIMS Forum 2018 Abstract P027.
Fingolimod cuts pediatric MS relapse rate more than interferon beta-1a
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.
A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.
The phase 3 PARADIGMS study is the first international controlled trial to evaluate the safety and efficacy of fingolimod in pediatric and adolescent patients. Dr. Chitnis and her colleagues randomized 215 participants aged 10-17 years to up to 0.5 mg/day of fingolimod based on body weight or to a once-a-week intramuscular injection of 30 mcg of interferon beta-1a. The trial lasted 2 years and was followed by an open-label extension for an additional 5 years.
The annualized relapse rate was the primary endpoint. The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
MRI findings and outcomes associated with relapse were secondary endpoints. The researchers found that, compared with the interferon beta-1a group, patients randomized to fingolimod had fewer lesions identified on MRI: There was a 53% annualized reduction in new or newly enlarged T2 lesions and 66% decrease in gadolinium-enhancing T1 lesions.
“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”
Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.
To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.
Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.
Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”
The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
FROM ACTRIMS FORUM 2018
Key clinical point:
Major finding: The fingolimod group experienced 25 relapses in 180 patient-years, compared with 120 relapses in 163 patient-years in the interferon beta-1a group.
Study details: International, randomized, double-blind, parallel-group study of 215 people aged 10-17 years.
Disclosures: The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.
Source: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
Study finds rising use of newer DMTs in pediatric-onset MS
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
FROM ACTRIMS FORUM 2018
Key clinical point: Newer DMTs are often used in individuals with pediatric MS.
Major finding: Among pediatric MS patients, the first agent used was a newer DMT in 17% of cases.
Study details: A retrospective review of prospectively collected data on 1,023 pediatric patients with MS.
Disclosures: The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Source: Krysko K et al. ACTRIMS Forum 2018 Poster 68.
Barancik Prize winner to discuss MS biology advances
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
Two decades ago, multiple sclerosis researchers like the University of Cambridge’s, Robin Franklin, PhD, understood the crucial role of regeneration of the myelin coating on nerve fibers, and they knew the process went awry in MS patients. But, he recalled, “we knew very little about how remyelination came about and the processes that orchestrated it.”
Now, thanks in part to the work of Dr. Franklin’s team, research into remyelination is making tremendous advances. “We’ve begun to understand the mechanisms that are operating, and that is fundamental to devising new therapies,” he said in an interview. “You don’t develop effective new therapies unless you understand the underlying biology. Now, we’re on the brink of that biology leading to regenerative medicine in MS.”
Dr. Franklin is the winner of the international prize, which recognizes exceptional MS research and is administered by the National MS Society.
In recent years, Dr. Franklin and his colleagues have published multiple studies that reveal new details about the workings of myelin regeneration, especially the biology by which oligodendrocyte progenitor cells become new oligodendrocytes.
“There are simple steps in that process,” Dr. Franklin said. “What we’ve been able to do is decorate that simple model with a whole host of mechanisms that allow remyelination to take place.”
In 2011, Franklin and his colleagues published a study in rodents identifying the RXRg gene as a key promoter of remyelination, making it a potential target for therapy (Nat Neurosci. 2011;14:45-53).
“There’s still a lot more to be learned,” Dr. Franklin said, “but we’ve learned a sufficient amount that we can engage in a meaningful way with the pharmaceutical industry and MS clinicians to make regenerative medicines an effective component of the MS therapeutic armory.”
Dr. Franklin has no relevant disclosures.
FROM ACTRIMS FORUM 2018
Researcher’s talk will tackle aging and gut bacteria in MS
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
Germs, genes, and aging each play a role in the development of multiple sclerosis (MS), but researchers are still figuring out how they’re connected. Now, a speaker at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis will shed light on recent findings that offer new insight into a specific type of germ – gut bacteria.
Suhayl Dhib-Jalbut, MD, ACTRIMS’s former president, will highlight his team’s investigation into the links between aging and alterations in gut microbiota in MS during the Kenneth P. Johnson Memorial Lecture on Feb. 1 at the meeting in San Diego.
Dr. Dhib-Jalbut’s presentation will focus on findings of a study by his team that was published late last year in Proceedings of the National Academy of Sciences of the U.S.A. (Proc Natl Acad Sci U S A. 2017 Oct 31;114[44]:E9318-27).
As the study explains, Dr. Dhib-Jalbut and colleagues triggered spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice by disrupting gut bacteria during adolescence and early young adulthood. But the process of aging in the mice past early young adulthood suppressed EAE onset by boosting immunologic tolerance.
The findings in this animal model offer insight into why the incidence of MS peaks at ages 20-40 years in humans, he said. “The implication is that one can perhaps manipulate gut bacteria with antibiotics or other treatments to impact the course of MS.”
REPORTING FROM ACTRIMS FORUM 2018
ACTRIMS Forum 2018 highlights MS therapeutic targets
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
Current and future therapeutic targets will be the major focus of a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), according to the meeting’s scientific program committee chair.
As many as 1,000 attendees are expected at the ACTRIMS Forum in San Diego, Feb. 1-3, Dr. Segal said, and about 300 abstracts will be presented. “The idea is for the meeting to be academically rigorous and have a speaker roster composed of the thought leaders in the field to make it akin to more of a keystone symposium.”
The program begins on Feb. 1 with presentations from young investigators about Emerging Concepts in MS. The other sessions will feature discussions about the blood-brain barrier, lymphocytes, cutting-edge developments in MS research, microglia and macrophages, astrocytes, and oligodendrocytes and their precursors.
“The sessions will begin with an overview of the particular target and its role in MS,” Dr. Segal said. “For example, the blood-brain barrier session starts with an overview of the different cell types that maintain the barrier’s integrity and the different ways they could prevent inflammatory cells from entering the central nervous system and causing lesions.”
One presentation in that session, he said, will discuss lessons from research into the mechanism of action of natalizumab (Tysabri). Another presentation focuses on new adhesion molecules – a crucial component of the inflammatory system – that have been discovered in animal models and may lead to new blocking therapies, he said.
The discussion about lymphocytes – white blood cells – will include presentations about new and emerging therapies that deplete them in different ways, he said. “One talk is about alemtuzumab (Lemtrada), which blocks all lymphocytes and can make you susceptible to other autoimmune disorders. What does that mean about how MS is similar to or different than other autoimmune diseases?”
On the myelin front, he said, “there will be a number of talks about how we identify remyelinating agents for clinical trials and how can we enhance precursors of myelination and reconstitute the damaged myelin.”
Another session will look at astrocytes, the glial support cells that are attracting newfound attention. Researchers have known that they’re stimulated in MS, and now new research is suggesting they can cause damage, he said. “They might be a completely new target. There’s evidence that they can have a neuroprotective effect, but it depends on how they’re stimulated.”
Are we on the cusp of being able to reverse damage from MS? “The answers are highly speculative. Research is so unpredictable and clinical trials do take a while,” he said. Still, “we understand repair pathways better than we ever have, and there’s lots of exciting work being done in animal models. We’re closer than we ever have been, and I do believe those drugs will be tested in clinical trials, hopefully within the next 5-10 years.”
Dr. Segal disclosed receiving an investigator-initiated grant from Genentech and support from Mallinckrodt for a clinical trial.
FROM ACTRIMS FORUM 2018