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Erik Greb joined the staff of Neurology Reviews in January 2012. Since then, he has attended scientific conferences, conducted video interviews, and written about clinical research in multiple sclerosis, epilepsy, Parkinson's disease, Alzheimer's disease, stroke, and other neurologic disorders. In addition to news articles, Erik has written investigative stories about multiple sclerosis, headache, and epilepsy. He previously wrote about pharmaceutical manufacturing, drug formulation and delivery, quality assurance, and regulation for Pharmaceutical Technology.
Mutant huntingtin and neurofilament light are potential biomarkers in Huntington’s disease
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
REPORTING FROM AAN 2019
Key clinical point: Mutant huntingtin and plasma and cerebrospinal fluid levels of neurofilament light are useful potential biomarkers in Huntington’s disease.
Major finding: Levels of neurofilament light in plasma are correlated with those in cerebrospinal fluid.
Study details: A prospective, observational, longitudinal cohort study including 80 participants with and without Huntington’s disease.
Disclosures: This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
Source: Rodrigues FB et al. AAN 2019, Abstract S16.003.
Treatment for hepatitis C reduces risk of Parkinson’s disease
, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.
In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.
Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.
The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.
The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.
To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.
Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.
The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.
“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.
Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.
The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.
SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.
The findings of Lin et al. suggest a potentially modifiable hepatologic risk factor for Parkinson’s disease, Adolfo Ramirez-Zamora, MD, associate professor of neurology; Christopher W. Hess, MD, assistant professor of neurology; and David R. Nelson, MD, senior vice president for health affairs, all at the University of Florida in Gainesville, wrote in an accompanying editorial. Hepatitis C virus infection might enter the brain through the microvasculature and might induce microglial and macrophage-related inflammatory changes (JAMA Neurol. 2019 June 5. doi: 10.1001/jamaneurol.2019.1377).
Lin et al. estimated high diagnostic accuracy for Parkinson’s disease in their study. Nevertheless, clinical, neuroimaging, and pathological confirmation was unavailable, which is a limitation of their investigation, said Dr. Ramirez-Zamora and colleagues. “The diagnosis of Parkinson’s disease in early stages can be challenging, as other related conditions can mimic Parkinson’s disease, including cirrhosis-related parkinsonism. Moreover, using record-linkage systems excludes patients who did not seek medical advice or those who were misdiagnosed by symptoms alone, which may also underestimate the prevalence of Parkinson’s disease. Using population-based studies would be a more accurate method.”
Because interferon, which was the antiviral therapy used in this study, greatly affects the immune system and has a modest rate of eradicating viral hepatitis C infection, future research should examine the association between Parkinson’s disease and patients who cleared the virus, as well as patients who did not, said Dr. Ramirez-Zamora and colleagues. Such research could shed light on potential mechanisms of treatment response. Lin et al. did not examine the newer direct-acting antiviral therapies for hepatitis C virus infection, which cure more than 90% of patients. Nor did they analyze other well established lifestyle and demographic risk factors for developing the disease. In addition, “the authors could not generalize the results to those aged 75 years or older because of the substantially smaller number of patients in this age group,” said Dr. Ramirez-Zamora and colleagues.
Still, “identification of potentially treatable Parkinson’s disease risk factors presents a unique opportunity for treatment. Additional studies with detailed viral analysis and exposure are needed, including in other geographic and ethnic distributions,” they concluded.
The findings of Lin et al. suggest a potentially modifiable hepatologic risk factor for Parkinson’s disease, Adolfo Ramirez-Zamora, MD, associate professor of neurology; Christopher W. Hess, MD, assistant professor of neurology; and David R. Nelson, MD, senior vice president for health affairs, all at the University of Florida in Gainesville, wrote in an accompanying editorial. Hepatitis C virus infection might enter the brain through the microvasculature and might induce microglial and macrophage-related inflammatory changes (JAMA Neurol. 2019 June 5. doi: 10.1001/jamaneurol.2019.1377).
Lin et al. estimated high diagnostic accuracy for Parkinson’s disease in their study. Nevertheless, clinical, neuroimaging, and pathological confirmation was unavailable, which is a limitation of their investigation, said Dr. Ramirez-Zamora and colleagues. “The diagnosis of Parkinson’s disease in early stages can be challenging, as other related conditions can mimic Parkinson’s disease, including cirrhosis-related parkinsonism. Moreover, using record-linkage systems excludes patients who did not seek medical advice or those who were misdiagnosed by symptoms alone, which may also underestimate the prevalence of Parkinson’s disease. Using population-based studies would be a more accurate method.”
Because interferon, which was the antiviral therapy used in this study, greatly affects the immune system and has a modest rate of eradicating viral hepatitis C infection, future research should examine the association between Parkinson’s disease and patients who cleared the virus, as well as patients who did not, said Dr. Ramirez-Zamora and colleagues. Such research could shed light on potential mechanisms of treatment response. Lin et al. did not examine the newer direct-acting antiviral therapies for hepatitis C virus infection, which cure more than 90% of patients. Nor did they analyze other well established lifestyle and demographic risk factors for developing the disease. In addition, “the authors could not generalize the results to those aged 75 years or older because of the substantially smaller number of patients in this age group,” said Dr. Ramirez-Zamora and colleagues.
Still, “identification of potentially treatable Parkinson’s disease risk factors presents a unique opportunity for treatment. Additional studies with detailed viral analysis and exposure are needed, including in other geographic and ethnic distributions,” they concluded.
The findings of Lin et al. suggest a potentially modifiable hepatologic risk factor for Parkinson’s disease, Adolfo Ramirez-Zamora, MD, associate professor of neurology; Christopher W. Hess, MD, assistant professor of neurology; and David R. Nelson, MD, senior vice president for health affairs, all at the University of Florida in Gainesville, wrote in an accompanying editorial. Hepatitis C virus infection might enter the brain through the microvasculature and might induce microglial and macrophage-related inflammatory changes (JAMA Neurol. 2019 June 5. doi: 10.1001/jamaneurol.2019.1377).
Lin et al. estimated high diagnostic accuracy for Parkinson’s disease in their study. Nevertheless, clinical, neuroimaging, and pathological confirmation was unavailable, which is a limitation of their investigation, said Dr. Ramirez-Zamora and colleagues. “The diagnosis of Parkinson’s disease in early stages can be challenging, as other related conditions can mimic Parkinson’s disease, including cirrhosis-related parkinsonism. Moreover, using record-linkage systems excludes patients who did not seek medical advice or those who were misdiagnosed by symptoms alone, which may also underestimate the prevalence of Parkinson’s disease. Using population-based studies would be a more accurate method.”
Because interferon, which was the antiviral therapy used in this study, greatly affects the immune system and has a modest rate of eradicating viral hepatitis C infection, future research should examine the association between Parkinson’s disease and patients who cleared the virus, as well as patients who did not, said Dr. Ramirez-Zamora and colleagues. Such research could shed light on potential mechanisms of treatment response. Lin et al. did not examine the newer direct-acting antiviral therapies for hepatitis C virus infection, which cure more than 90% of patients. Nor did they analyze other well established lifestyle and demographic risk factors for developing the disease. In addition, “the authors could not generalize the results to those aged 75 years or older because of the substantially smaller number of patients in this age group,” said Dr. Ramirez-Zamora and colleagues.
Still, “identification of potentially treatable Parkinson’s disease risk factors presents a unique opportunity for treatment. Additional studies with detailed viral analysis and exposure are needed, including in other geographic and ethnic distributions,” they concluded.
, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.
In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.
Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.
The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.
The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.
To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.
Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.
The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.
“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.
Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.
The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.
SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.
, according to a cohort study published online June 5 in JAMA Neurology. The results provide evidence that hepatitis C virus is a risk factor for Parkinson’s disease.
In the past several years, epidemiologic studies have suggested an association between hepatitis C virus infection and Parkinson’s disease. A study published in 2017, however, found no association between the two. In addition, these investigations did not consider antiviral therapy as a potential modifying factor.
Wey-Yil Lin, MD, a neurologist at Landseed International Hospital in Taoyuan, Taiwan, and colleagues examined claims data from the Taiwan National Health Insurance Research Database to identify the risk of incident Parkinson’s disease in patients with hepatitis C virus infection who received antiviral treatment, compared with those who did not receive treatment.
The investigators selected all patients with a new diagnosis of hepatitis C virus infection with or without hepatitis from January 1, 2003, to December 31, 2013. They excluded patients who were aged 20 years or younger; had Parkinson’s disease, dementia, or stroke; or had had major hepatic diseases on the index date. To ensure that treated patients had had an effective course of therapy, the researchers excluded patients who were lost to follow-up within 6 months of the index date, received antiviral therapy for fewer than 16 weeks, or developed Parkinson’s disease within 6 months of the index date.
The primary outcome was incident Parkinson’s disease. Dr. Lin and colleagues excluded participants with a diagnosis of stroke and dementia before the index date to reduce the possibility of enrolling participants with secondary and atypical parkinsonism.
To minimize the potential selection bias to which observational studies are subject, the investigators performed propensity score matching with sex, age, comorbidities, and medication as covariates. This method was intended to create treated and untreated cohorts with comparable characteristics.
Dr. Lin and colleagues included 188,152 patients in their analysis. After matching, each group included 39,936 participants. In the group that received antiviral treatment, 45.0% of participants were female, and mean age was 52.8 years. In the untreated group, 44.4% of participants were female, and mean age was 52.5 years.
The incidence density of Parkinson’s disease per 1,000 person-years was 1.00 in the treated group and 1.39 in the untreated group. The difference in risk of Parkinson’s disease between the treated and untreated groups was statistically significant at year 5 of follow-up (hazard ratio [HR], 0.75) and at the end of the cohort (HR, 0.71). The risk did not differ significantly at year 1 and year 3, however. A subgroup analysis found a greater benefit of antiviral therapy among patients who concurrently used dihydropyridine calcium channel blockers.
“To our knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson’s disease in patients with chronic hepatitis C viral infection,” said Dr. Lin and colleagues. Although it is possible that interferon-based antiviral therapy directly protected against the development of Parkinson’s disease, the short time of exposure to the antiviral agent “makes protecting against Parkinson’s disease development in 5 years less likely,” they added.
Among the study limitations that the authors acknowledged was the lack of data about hepatic function profile, serum virologic response, viral genotype, and hepatitis C virus RNA-level. The database that the investigators used also lacked data about behavioral factors (e.g., smoking status, coffee consumption, and alcohol consumption) that may have affected the incidence of Parkinson’s disease in the cohort. Investigations with longer follow-up periods will be needed to provide clearer information, they concluded.
The authors reported no conflicts of interest. The study was funded by grants from Chang Gung Medical Research Fund and from Chang Gung Memorial Hospital.
SOURCE: Lin W-Y et al. JAMA Neurol. 2019 Jun 5. doi: 10.1001/jamaneurol.2019.1368.
FROM JAMA NEUROLOGY
Stewart Tepper: Emgality approval ‘very exciting’
The drug, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), is administered by self-injection in 300-mg doses.
Galcanezumab is the first medication for episodic cluster headache that reduces the frequency of attacks, the agency said in an announcement.
Cluster headache can be more intense than migraine. The pain is unilateral and occurs in the orbital, supraorbital, or temporal regions. It reaches its peak intensity within 5-10 minutes and generally lasts for 30-90 minutes. Symptoms include a burning sensation, conjunctival injection, rhinorrhea, and photosensitivity. Patients often have one to three of these headaches per day, and the headaches appear to be linked to the circadian rhythm. An episodic cluster cycle can last for weeks to months of daily or near daily attacks.
A study presented at the recent meeting of the American Academy of Neurology provided evidence of the drug’s efficacy in cluster headache. In this trial, researchers randomized 106 patients with episodic cluster headache to galcanezumab or placebo. The baseline cluster headache frequency was 17.3 attacks per week, and galcanezumab reduced this frequency to 9.1 attacks per week, compared with 12.1 attacks per week with placebo. The most common side effect reported in this and other clinical trials was injection-site reactions.
Galcanezumab entails a risk of hypersensitivity reactions, according to the FDA. These reactions may occur several days after administration and may be prolonged. “If a serious hypersensitivity reaction occurs, treatment should be discontinued,” the agency said.
“It’s a very exciting day. There had never been a drug approved for prevention of cluster headache,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.
It is difficult to achieve therapeutic concentrations of current preventive medications that do not have FDA approval for this indication, such as verapamil, lithium, or antiepileptic drugs. Galcanezumab, in contrast, works quickly. It is important to note that the approval was for preventive treatment of episodic cluster headache, not for prevention of chronic cluster headache, and not for acute treatment, Dr. Tepper said.
“It’s important to get optimal therapy for cluster headache. It is one of the most disabling, terrible disorders on Earth,” Dr. Tepper said. “The importance [of this approval] cannot be overestimated.”
When asked for comment, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said “If this monoclonal antibody to the CGRP ligand works as well in real life as in the trial, it will be an important advance in the treatment of cluster headache.”
Prior to the approval of galcanezumab, noninvasive vagal nerve stimulation was approved in November 2018 for adjunctive use in the preventive treatment of cluster headache in adults.
The FDA granted the application for galcanezumab using a Priority Review and Breakthrough Therapy designation. The agency approved galcanezumab for the preventive treatment of migraine in adults in September 2018. The drug appears to have a similar safety profile in both patient populations. Eli Lilly, which is based in Indianapolis, Indiana, manufactures the drug.
This article was updated June 5, 2019.
The drug, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), is administered by self-injection in 300-mg doses.
Galcanezumab is the first medication for episodic cluster headache that reduces the frequency of attacks, the agency said in an announcement.
Cluster headache can be more intense than migraine. The pain is unilateral and occurs in the orbital, supraorbital, or temporal regions. It reaches its peak intensity within 5-10 minutes and generally lasts for 30-90 minutes. Symptoms include a burning sensation, conjunctival injection, rhinorrhea, and photosensitivity. Patients often have one to three of these headaches per day, and the headaches appear to be linked to the circadian rhythm. An episodic cluster cycle can last for weeks to months of daily or near daily attacks.
A study presented at the recent meeting of the American Academy of Neurology provided evidence of the drug’s efficacy in cluster headache. In this trial, researchers randomized 106 patients with episodic cluster headache to galcanezumab or placebo. The baseline cluster headache frequency was 17.3 attacks per week, and galcanezumab reduced this frequency to 9.1 attacks per week, compared with 12.1 attacks per week with placebo. The most common side effect reported in this and other clinical trials was injection-site reactions.
Galcanezumab entails a risk of hypersensitivity reactions, according to the FDA. These reactions may occur several days after administration and may be prolonged. “If a serious hypersensitivity reaction occurs, treatment should be discontinued,” the agency said.
“It’s a very exciting day. There had never been a drug approved for prevention of cluster headache,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.
It is difficult to achieve therapeutic concentrations of current preventive medications that do not have FDA approval for this indication, such as verapamil, lithium, or antiepileptic drugs. Galcanezumab, in contrast, works quickly. It is important to note that the approval was for preventive treatment of episodic cluster headache, not for prevention of chronic cluster headache, and not for acute treatment, Dr. Tepper said.
“It’s important to get optimal therapy for cluster headache. It is one of the most disabling, terrible disorders on Earth,” Dr. Tepper said. “The importance [of this approval] cannot be overestimated.”
When asked for comment, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said “If this monoclonal antibody to the CGRP ligand works as well in real life as in the trial, it will be an important advance in the treatment of cluster headache.”
Prior to the approval of galcanezumab, noninvasive vagal nerve stimulation was approved in November 2018 for adjunctive use in the preventive treatment of cluster headache in adults.
The FDA granted the application for galcanezumab using a Priority Review and Breakthrough Therapy designation. The agency approved galcanezumab for the preventive treatment of migraine in adults in September 2018. The drug appears to have a similar safety profile in both patient populations. Eli Lilly, which is based in Indianapolis, Indiana, manufactures the drug.
This article was updated June 5, 2019.
The drug, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), is administered by self-injection in 300-mg doses.
Galcanezumab is the first medication for episodic cluster headache that reduces the frequency of attacks, the agency said in an announcement.
Cluster headache can be more intense than migraine. The pain is unilateral and occurs in the orbital, supraorbital, or temporal regions. It reaches its peak intensity within 5-10 minutes and generally lasts for 30-90 minutes. Symptoms include a burning sensation, conjunctival injection, rhinorrhea, and photosensitivity. Patients often have one to three of these headaches per day, and the headaches appear to be linked to the circadian rhythm. An episodic cluster cycle can last for weeks to months of daily or near daily attacks.
A study presented at the recent meeting of the American Academy of Neurology provided evidence of the drug’s efficacy in cluster headache. In this trial, researchers randomized 106 patients with episodic cluster headache to galcanezumab or placebo. The baseline cluster headache frequency was 17.3 attacks per week, and galcanezumab reduced this frequency to 9.1 attacks per week, compared with 12.1 attacks per week with placebo. The most common side effect reported in this and other clinical trials was injection-site reactions.
Galcanezumab entails a risk of hypersensitivity reactions, according to the FDA. These reactions may occur several days after administration and may be prolonged. “If a serious hypersensitivity reaction occurs, treatment should be discontinued,” the agency said.
“It’s a very exciting day. There had never been a drug approved for prevention of cluster headache,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth and director of the Dartmouth Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.
It is difficult to achieve therapeutic concentrations of current preventive medications that do not have FDA approval for this indication, such as verapamil, lithium, or antiepileptic drugs. Galcanezumab, in contrast, works quickly. It is important to note that the approval was for preventive treatment of episodic cluster headache, not for prevention of chronic cluster headache, and not for acute treatment, Dr. Tepper said.
“It’s important to get optimal therapy for cluster headache. It is one of the most disabling, terrible disorders on Earth,” Dr. Tepper said. “The importance [of this approval] cannot be overestimated.”
When asked for comment, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said “If this monoclonal antibody to the CGRP ligand works as well in real life as in the trial, it will be an important advance in the treatment of cluster headache.”
Prior to the approval of galcanezumab, noninvasive vagal nerve stimulation was approved in November 2018 for adjunctive use in the preventive treatment of cluster headache in adults.
The FDA granted the application for galcanezumab using a Priority Review and Breakthrough Therapy designation. The agency approved galcanezumab for the preventive treatment of migraine in adults in September 2018. The drug appears to have a similar safety profile in both patient populations. Eli Lilly, which is based in Indianapolis, Indiana, manufactures the drug.
This article was updated June 5, 2019.
Switching from interferon beta-1a to alemtuzumab improves MS outcomes
SEATTLE – , according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.
The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.
Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.
In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.
In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.
Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.
SEATTLE – , according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.
The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.
Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.
In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.
In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.
Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.
SEATTLE – , according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.
The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.
Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.
In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.
In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.
Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.
REPORTING FROM CMSC 2019
High-efficacy DMTs may reduce depressive symptoms in MS
SEATTLE – , according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.
Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.
To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.
The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.
In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.
The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.
In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.
In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.
Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.
The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.
SEATTLE – , according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.
Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.
To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.
The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.
In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.
The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.
In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.
In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.
Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.
The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.
SEATTLE – , according to an interim analysis described at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Depression, a common psychiatric comorbidity in MS, is associated with excess morbidity and mortality in that population. Treatment with disease-modifying therapy (DMT) could influence the cause and symptoms of depression.
Youkyung S. Roh, a medical student at Johns Hopkins University in Baltimore, and colleagues hypothesized that lower-efficacy DMTs may increase the risk of depression, whereas higher-efficacy DMTs may have antidepressive properties, possibly because of their anti-inflammatory effects.
To test this hypothesis, Ms. Roh and her colleagues examined data from MS Partners Advancing Technology and Health Solutions (MS PATHS), an ongoing, 10-site, longitudinal study. They compared the rates of change in depressive symptom severity, as measured by the Quality of Life in Neurological Disorders (Neuro-QoL) depression subscale, between patients initiating a lower-efficacy DMT and those initiating a higher-efficacy DMT. Eligible participants had relapsing-remitting MS, were new initiators of DMTs, and completed baseline and follow-up Neuro-QoL depression scales. The researchers defined lower-efficacy DMTs as interferons, glatiramer acetate, fingolimod, and dimethyl fumarate. Higher-efficacy DMTs were defined as natalizumab, rituximab, ocrelizumab, and alemtuzumab.
The investigators used multivariable-adjusted, mixed-effects regression models to compare the rates of change in Neuro-QoL depression scores for patients with MS who were initiating higher-efficacy DMTs versus those initiating lower-efficacy DMTs. Secondary analyses excluded interferons from the lower-efficacy DMT category.
In addition, the investigators compared the rates of depression between therapies within each class of DMT efficacy. Other analyses were stratified by sex, race, disability status, and antidepressant use.
The investigators’ interim analyses included 1,501 participants who initiated a new therapy and who had baseline and follow-up Neuro-QoL depression scores. The mean age of the study population was 45.1 years, and 76% of participants were women. Average follow-up duration was just under 1 year.
In all, 922 participants initiated lower-efficacy DMTs, and 579 participants initiated higher-efficacy DMTs. In preliminary analyses, initiation of higher-efficacy DMT was associated with a multivariable-adjusted 0.58-points/year reduction in Neuro-QoL depression scores, compared with initiation of lower-efficacy DMT. The result was statistically significant.
In addition, results were consistent in analyses that excluded interferons from the category of lower-efficacy DMTs. In those analyses, the reduction in depression scores was 0.63 points/year, which was also statistically significant.
Analyses incorporating additional follow-up data from this cohort are ongoing, said the authors.
The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported no disclosures or conflicts of interest.
REPORTING FROM CMSC 2019
Patients with MS who consider using marijuana are more likely to engage in risky behaviors
SEATTLE – based on survey results presented at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
“Discussing marijuana use with patients should include discussion of better health behaviors overall,” said Stacey S. Cofield, PhD, associate professor of biostatistics at the University of Alabama at Birmingham.
In August 2014, Dr. Cofield and colleagues invited 12,260 active participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry to complete an online, anonymous questionnaire about current behaviors and attitudes regarding marijuana use and legality. Marijuana use was defined as smoking or ingesting marijuana, as well as using controlled substances derived from marijuana or synthetic marijuana. The questionnaire also asked participants about other potentially risky health behaviors, including alcohol consumption, smoking, and seat belt use.
About 78% of the 5,481 survey respondents were women. The median age at response time was 57 years, and median age at diagnosis was 37 years. In addition, 26.5% reported having active relapsing disease, 42.9% reported stable relapsing disease (that is, no relapse in at least 2 years), 20.9% reported progressive disease that formerly had been relapsing, and 9.8% reported progressive disease without relapses.
Most respondents (91.5%) thought that marijuana should be legal, 58.1% thought that it should require a prescription, and 52.9% considered using it for MS. Although 25.4% of respondents have used marijuana for their MS, 20.0% had discussed it with their doctor, and 16.1% were currently using some form of marijuana.
Nearly half of respondents, 48%, reported never using tobacco, 39.4% were former smokers, and 12.5% were current smokers. About 25% reported never consuming alcohol, with 32% consuming it monthly or less, 19% consuming it two to four times per month, and 24% consuming alcohol at least weekly. Approximately 93% of participants reported always wearing a seat belt, 4.7% nearly always used it, and more than 1% used it sometimes, seldom, or never, respectively.
When Dr. Cofield and colleagues adjusted the data for age and gender, they found that current marijuana users and those who said they had considered marijuana use were significantly more likely to be current tobacco users and to consume alcohol; they were nominally less likely to wear seat belts.
NARCOMS is funded in part by the CMSC and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.
SEATTLE – based on survey results presented at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
“Discussing marijuana use with patients should include discussion of better health behaviors overall,” said Stacey S. Cofield, PhD, associate professor of biostatistics at the University of Alabama at Birmingham.
In August 2014, Dr. Cofield and colleagues invited 12,260 active participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry to complete an online, anonymous questionnaire about current behaviors and attitudes regarding marijuana use and legality. Marijuana use was defined as smoking or ingesting marijuana, as well as using controlled substances derived from marijuana or synthetic marijuana. The questionnaire also asked participants about other potentially risky health behaviors, including alcohol consumption, smoking, and seat belt use.
About 78% of the 5,481 survey respondents were women. The median age at response time was 57 years, and median age at diagnosis was 37 years. In addition, 26.5% reported having active relapsing disease, 42.9% reported stable relapsing disease (that is, no relapse in at least 2 years), 20.9% reported progressive disease that formerly had been relapsing, and 9.8% reported progressive disease without relapses.
Most respondents (91.5%) thought that marijuana should be legal, 58.1% thought that it should require a prescription, and 52.9% considered using it for MS. Although 25.4% of respondents have used marijuana for their MS, 20.0% had discussed it with their doctor, and 16.1% were currently using some form of marijuana.
Nearly half of respondents, 48%, reported never using tobacco, 39.4% were former smokers, and 12.5% were current smokers. About 25% reported never consuming alcohol, with 32% consuming it monthly or less, 19% consuming it two to four times per month, and 24% consuming alcohol at least weekly. Approximately 93% of participants reported always wearing a seat belt, 4.7% nearly always used it, and more than 1% used it sometimes, seldom, or never, respectively.
When Dr. Cofield and colleagues adjusted the data for age and gender, they found that current marijuana users and those who said they had considered marijuana use were significantly more likely to be current tobacco users and to consume alcohol; they were nominally less likely to wear seat belts.
NARCOMS is funded in part by the CMSC and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.
SEATTLE – based on survey results presented at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
“Discussing marijuana use with patients should include discussion of better health behaviors overall,” said Stacey S. Cofield, PhD, associate professor of biostatistics at the University of Alabama at Birmingham.
In August 2014, Dr. Cofield and colleagues invited 12,260 active participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry to complete an online, anonymous questionnaire about current behaviors and attitudes regarding marijuana use and legality. Marijuana use was defined as smoking or ingesting marijuana, as well as using controlled substances derived from marijuana or synthetic marijuana. The questionnaire also asked participants about other potentially risky health behaviors, including alcohol consumption, smoking, and seat belt use.
About 78% of the 5,481 survey respondents were women. The median age at response time was 57 years, and median age at diagnosis was 37 years. In addition, 26.5% reported having active relapsing disease, 42.9% reported stable relapsing disease (that is, no relapse in at least 2 years), 20.9% reported progressive disease that formerly had been relapsing, and 9.8% reported progressive disease without relapses.
Most respondents (91.5%) thought that marijuana should be legal, 58.1% thought that it should require a prescription, and 52.9% considered using it for MS. Although 25.4% of respondents have used marijuana for their MS, 20.0% had discussed it with their doctor, and 16.1% were currently using some form of marijuana.
Nearly half of respondents, 48%, reported never using tobacco, 39.4% were former smokers, and 12.5% were current smokers. About 25% reported never consuming alcohol, with 32% consuming it monthly or less, 19% consuming it two to four times per month, and 24% consuming alcohol at least weekly. Approximately 93% of participants reported always wearing a seat belt, 4.7% nearly always used it, and more than 1% used it sometimes, seldom, or never, respectively.
When Dr. Cofield and colleagues adjusted the data for age and gender, they found that current marijuana users and those who said they had considered marijuana use were significantly more likely to be current tobacco users and to consume alcohol; they were nominally less likely to wear seat belts.
NARCOMS is funded in part by the CMSC and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.
REPORTING FROM CMSC 2019
Fingolimod reduces MS disease activity, compared with glatiramer acetate
SEATTLE – according to a controlled, head-to-head study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Investigations that directly compare the efficacy and safety of disease-modifying therapies can provide valuable information that influences treatment decisions in clinical practice. Phase 3 clinical trials indicated that oral fingolimod (0.5 mg/day) is more effective than placebo and interferon beta-1a in patients with multiple sclerosis (MS). However, how fingolimod compares with glatiramer acetate is unclear.
Bruce A. C. Cree, MD, PhD, clinical research director of the Multiple Sclerosis Center at the University of California, San Francisco, and colleagues sought to compare the efficacy of once-daily 0.5 mg and 0.25 mg oral fingolimod with that of once-daily 20 mg subcutaneous injections of glatiramer acetate in reducing disease activity over 12 months in patients with relapsing remitting MS. They conducted the phase 3b, multicenter, rater- and dose-blinded ASSESS study. Dr. Cree and colleagues randomized 352 eligible patients to 0.5 mg/day of oral fingolimod, 370 patients to 0.25 mg/day of oral fingolimod, and 342 patients to 20 mg/day of subcutaneous glatiramer acetate. They examined the potential superiority of each fingolimod dose to glatiramer acetate separately, starting with the higher dose. The primary endpoint was the change in annualized relapse rate, and the secondary endpoints were MRI measures of disease activity at 12 months. Finally, the investigators evaluated safety and tolerability.
A total of 859 patients (80.7%) completed the study. Over 12 months, the annualized relapse rate was 0.153 for the 0.5 mg fingolimod group and 0.258 for the glatiramer acetate group (relative reduction, 40.7%). The 0.25-mg dose of fingolimod achieved a numerical RR of 14.6%, but this result was not statistically significant. Compared with glatiramer acetate, the 0.5-mg and 0.25-mg doses of fingolimod significantly reduced the mean number of new or newly enlarged T2 lesions (RR, 54.4% and 42.1%, respectively) and gadolinium-enhancing T1 lesions (RR, 55.6% for both doses).
The adverse events that participants reported for both doses of fingolimod were consistent with the treatment’s known safety profile. More discontinuations were reported with glatiramer acetate than with fingolimod. These events mainly resulted from injection-related adverse events, consent withdrawal, and unsatisfactory therapeutic effects. Dr. Cree and colleagues plan to report the results of additional cognitive and functional system evaluations, including the Symbol Digit Modalities Test and the MS Functional Composite, later this year.
The study was not supported by outside funding. Dr. Cree reported receiving consulting fees from AbbVie, Akili, Biogen, EMD Serono, and Novartis.
[email protected]
SEATTLE – according to a controlled, head-to-head study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Investigations that directly compare the efficacy and safety of disease-modifying therapies can provide valuable information that influences treatment decisions in clinical practice. Phase 3 clinical trials indicated that oral fingolimod (0.5 mg/day) is more effective than placebo and interferon beta-1a in patients with multiple sclerosis (MS). However, how fingolimod compares with glatiramer acetate is unclear.
Bruce A. C. Cree, MD, PhD, clinical research director of the Multiple Sclerosis Center at the University of California, San Francisco, and colleagues sought to compare the efficacy of once-daily 0.5 mg and 0.25 mg oral fingolimod with that of once-daily 20 mg subcutaneous injections of glatiramer acetate in reducing disease activity over 12 months in patients with relapsing remitting MS. They conducted the phase 3b, multicenter, rater- and dose-blinded ASSESS study. Dr. Cree and colleagues randomized 352 eligible patients to 0.5 mg/day of oral fingolimod, 370 patients to 0.25 mg/day of oral fingolimod, and 342 patients to 20 mg/day of subcutaneous glatiramer acetate. They examined the potential superiority of each fingolimod dose to glatiramer acetate separately, starting with the higher dose. The primary endpoint was the change in annualized relapse rate, and the secondary endpoints were MRI measures of disease activity at 12 months. Finally, the investigators evaluated safety and tolerability.
A total of 859 patients (80.7%) completed the study. Over 12 months, the annualized relapse rate was 0.153 for the 0.5 mg fingolimod group and 0.258 for the glatiramer acetate group (relative reduction, 40.7%). The 0.25-mg dose of fingolimod achieved a numerical RR of 14.6%, but this result was not statistically significant. Compared with glatiramer acetate, the 0.5-mg and 0.25-mg doses of fingolimod significantly reduced the mean number of new or newly enlarged T2 lesions (RR, 54.4% and 42.1%, respectively) and gadolinium-enhancing T1 lesions (RR, 55.6% for both doses).
The adverse events that participants reported for both doses of fingolimod were consistent with the treatment’s known safety profile. More discontinuations were reported with glatiramer acetate than with fingolimod. These events mainly resulted from injection-related adverse events, consent withdrawal, and unsatisfactory therapeutic effects. Dr. Cree and colleagues plan to report the results of additional cognitive and functional system evaluations, including the Symbol Digit Modalities Test and the MS Functional Composite, later this year.
The study was not supported by outside funding. Dr. Cree reported receiving consulting fees from AbbVie, Akili, Biogen, EMD Serono, and Novartis.
[email protected]
SEATTLE – according to a controlled, head-to-head study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
Investigations that directly compare the efficacy and safety of disease-modifying therapies can provide valuable information that influences treatment decisions in clinical practice. Phase 3 clinical trials indicated that oral fingolimod (0.5 mg/day) is more effective than placebo and interferon beta-1a in patients with multiple sclerosis (MS). However, how fingolimod compares with glatiramer acetate is unclear.
Bruce A. C. Cree, MD, PhD, clinical research director of the Multiple Sclerosis Center at the University of California, San Francisco, and colleagues sought to compare the efficacy of once-daily 0.5 mg and 0.25 mg oral fingolimod with that of once-daily 20 mg subcutaneous injections of glatiramer acetate in reducing disease activity over 12 months in patients with relapsing remitting MS. They conducted the phase 3b, multicenter, rater- and dose-blinded ASSESS study. Dr. Cree and colleagues randomized 352 eligible patients to 0.5 mg/day of oral fingolimod, 370 patients to 0.25 mg/day of oral fingolimod, and 342 patients to 20 mg/day of subcutaneous glatiramer acetate. They examined the potential superiority of each fingolimod dose to glatiramer acetate separately, starting with the higher dose. The primary endpoint was the change in annualized relapse rate, and the secondary endpoints were MRI measures of disease activity at 12 months. Finally, the investigators evaluated safety and tolerability.
A total of 859 patients (80.7%) completed the study. Over 12 months, the annualized relapse rate was 0.153 for the 0.5 mg fingolimod group and 0.258 for the glatiramer acetate group (relative reduction, 40.7%). The 0.25-mg dose of fingolimod achieved a numerical RR of 14.6%, but this result was not statistically significant. Compared with glatiramer acetate, the 0.5-mg and 0.25-mg doses of fingolimod significantly reduced the mean number of new or newly enlarged T2 lesions (RR, 54.4% and 42.1%, respectively) and gadolinium-enhancing T1 lesions (RR, 55.6% for both doses).
The adverse events that participants reported for both doses of fingolimod were consistent with the treatment’s known safety profile. More discontinuations were reported with glatiramer acetate than with fingolimod. These events mainly resulted from injection-related adverse events, consent withdrawal, and unsatisfactory therapeutic effects. Dr. Cree and colleagues plan to report the results of additional cognitive and functional system evaluations, including the Symbol Digit Modalities Test and the MS Functional Composite, later this year.
The study was not supported by outside funding. Dr. Cree reported receiving consulting fees from AbbVie, Akili, Biogen, EMD Serono, and Novartis.
[email protected]
REPORTING FROM CMSC 2019
Key clinical point: Fingolimod is superior to glatiramer acetate in reducing disease activity in relapsing remitting multiple sclerosis.
Major finding: The 0.5-mg/day dose of fingolimod reduced the annualized relapse rate by approximately 41%, compared with glatiramer acetate.
Study details: A randomized, phase 3 study of 859 patients with relapsing remitting multiple sclerosis.
Disclosures: The study had no sponsorship. Dr. Cree reported receiving consulting fees from AbbVie, Akili, Biogen, EMD Serono, and Novartis.
Adherence to oral treatments for MS is poor
Seattle – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These results indicate “poor adherence to currently available oral medications” and “may imply a need for treatments with dosing regimens that facilitate adherence,” said Jacqueline Nicholas, MD, MPH, a clinical neuroimmunologist at the Ohio MS Center in Columbus, and colleagues.
Research has found that lapses in MS treatment regimens and discontinuation of disease-modifying therapy are associated with an increased likelihood of relapse. Few studies, however, have examined lapses in oral therapy and discontinuation of oral treatments in patients with MS. To address this gap, Dr. Nicholas and colleagues conducted a retrospective administrative claims study using data from the IQVIA RWD Adjudicated Claims – USA database.
The researchers examined claims filed between July 1, 2012, and June 30, 2017. Eligible participants were aged 18-63 years and had two or more MS diagnosis claims (i.e., ICD-9-CM code: 340.xx and ICD-10-CM code: G35) between July 1, 2013, and June 30, 2015. Participants also had one or more once- or twice-daily oral disease-modifying drug (DMD) claims between July 1, 2013, and June 30, 2015; continuous eligibility with commercial insurance for 1 year before (i.e., baseline) and 2 years after (i.e., follow-up) oral DMD initiation; and no oral DMD use during baseline.
The investigators defined the longest lapse in therapy as the number of days between the lapsing of the supply of the prior prescription and the fulfillment of a new prescription (i.e., the period during which no DMD was available, based on medical or pharmacy claims). Discontinuation was defined as cessation of the oral DMD for a minimum of 60 days without reinitiation (i.e., discontinuing treatment or switching therapy).
In all, 4,193 patients met the eligibility criteria. The population’s mean age was 45.4 years, and 76.3% of the patients were female. The mean duration of the longest lapse was 35.6 days. The longest lapse was 0 to fewer than 15 days for 44.6% of patients, 15 to fewer than 30 days for 25.6% of patients, 30 to fewer than 45 days for 11.0% of patients, 45 to fewer than 60 days for 5.2% of patients, 60 to fewer than 75 days for 3.5% of patients, 75 to fewer than 90 days for 1.7% of patients, and 90 or more days for 8.3% of patients. In addition, 45.2% of patients discontinued oral DMD treatment, and the mean time to discontinuation was 249.0 days.
The authors received no financial support for this study. Dr. Nicholas reported receiving grant support from EMD Serono.
SOURCE: Nicholas J et al. CMSC 2019. Abstract DXT34.
Seattle – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These results indicate “poor adherence to currently available oral medications” and “may imply a need for treatments with dosing regimens that facilitate adherence,” said Jacqueline Nicholas, MD, MPH, a clinical neuroimmunologist at the Ohio MS Center in Columbus, and colleagues.
Research has found that lapses in MS treatment regimens and discontinuation of disease-modifying therapy are associated with an increased likelihood of relapse. Few studies, however, have examined lapses in oral therapy and discontinuation of oral treatments in patients with MS. To address this gap, Dr. Nicholas and colleagues conducted a retrospective administrative claims study using data from the IQVIA RWD Adjudicated Claims – USA database.
The researchers examined claims filed between July 1, 2012, and June 30, 2017. Eligible participants were aged 18-63 years and had two or more MS diagnosis claims (i.e., ICD-9-CM code: 340.xx and ICD-10-CM code: G35) between July 1, 2013, and June 30, 2015. Participants also had one or more once- or twice-daily oral disease-modifying drug (DMD) claims between July 1, 2013, and June 30, 2015; continuous eligibility with commercial insurance for 1 year before (i.e., baseline) and 2 years after (i.e., follow-up) oral DMD initiation; and no oral DMD use during baseline.
The investigators defined the longest lapse in therapy as the number of days between the lapsing of the supply of the prior prescription and the fulfillment of a new prescription (i.e., the period during which no DMD was available, based on medical or pharmacy claims). Discontinuation was defined as cessation of the oral DMD for a minimum of 60 days without reinitiation (i.e., discontinuing treatment or switching therapy).
In all, 4,193 patients met the eligibility criteria. The population’s mean age was 45.4 years, and 76.3% of the patients were female. The mean duration of the longest lapse was 35.6 days. The longest lapse was 0 to fewer than 15 days for 44.6% of patients, 15 to fewer than 30 days for 25.6% of patients, 30 to fewer than 45 days for 11.0% of patients, 45 to fewer than 60 days for 5.2% of patients, 60 to fewer than 75 days for 3.5% of patients, 75 to fewer than 90 days for 1.7% of patients, and 90 or more days for 8.3% of patients. In addition, 45.2% of patients discontinued oral DMD treatment, and the mean time to discontinuation was 249.0 days.
The authors received no financial support for this study. Dr. Nicholas reported receiving grant support from EMD Serono.
SOURCE: Nicholas J et al. CMSC 2019. Abstract DXT34.
Seattle – , according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These results indicate “poor adherence to currently available oral medications” and “may imply a need for treatments with dosing regimens that facilitate adherence,” said Jacqueline Nicholas, MD, MPH, a clinical neuroimmunologist at the Ohio MS Center in Columbus, and colleagues.
Research has found that lapses in MS treatment regimens and discontinuation of disease-modifying therapy are associated with an increased likelihood of relapse. Few studies, however, have examined lapses in oral therapy and discontinuation of oral treatments in patients with MS. To address this gap, Dr. Nicholas and colleagues conducted a retrospective administrative claims study using data from the IQVIA RWD Adjudicated Claims – USA database.
The researchers examined claims filed between July 1, 2012, and June 30, 2017. Eligible participants were aged 18-63 years and had two or more MS diagnosis claims (i.e., ICD-9-CM code: 340.xx and ICD-10-CM code: G35) between July 1, 2013, and June 30, 2015. Participants also had one or more once- or twice-daily oral disease-modifying drug (DMD) claims between July 1, 2013, and June 30, 2015; continuous eligibility with commercial insurance for 1 year before (i.e., baseline) and 2 years after (i.e., follow-up) oral DMD initiation; and no oral DMD use during baseline.
The investigators defined the longest lapse in therapy as the number of days between the lapsing of the supply of the prior prescription and the fulfillment of a new prescription (i.e., the period during which no DMD was available, based on medical or pharmacy claims). Discontinuation was defined as cessation of the oral DMD for a minimum of 60 days without reinitiation (i.e., discontinuing treatment or switching therapy).
In all, 4,193 patients met the eligibility criteria. The population’s mean age was 45.4 years, and 76.3% of the patients were female. The mean duration of the longest lapse was 35.6 days. The longest lapse was 0 to fewer than 15 days for 44.6% of patients, 15 to fewer than 30 days for 25.6% of patients, 30 to fewer than 45 days for 11.0% of patients, 45 to fewer than 60 days for 5.2% of patients, 60 to fewer than 75 days for 3.5% of patients, 75 to fewer than 90 days for 1.7% of patients, and 90 or more days for 8.3% of patients. In addition, 45.2% of patients discontinued oral DMD treatment, and the mean time to discontinuation was 249.0 days.
The authors received no financial support for this study. Dr. Nicholas reported receiving grant support from EMD Serono.
SOURCE: Nicholas J et al. CMSC 2019. Abstract DXT34.
REPORTING FROM CMSC 2019
Extended-release arbaclofen reduces MS-related spasticity
SEATTLE – (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.
Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABAB receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.
Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.
Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).
Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.
The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.
SEATTLE – (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.
Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABAB receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.
Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.
Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).
Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.
The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.
SEATTLE – (MS), according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. The regimen is well tolerated.
Spasticity is common in MS, and the traditional treatment is oral baclofen, a GABAB receptor agonist. Therapeutic doses of baclofen may cause side effects that decrease adherence, however. Arbaclofen is a more active R-enantiomer of baclofen, which is a racemic mixture. Arbaclofen extended-release (ER) tablets enable twice-daily administration, which reduces dosing frequency and may decrease the rate of adverse events.
Daniel Kantor, MD, a faculty member at Florida Atlantic University in Boca Raton, and colleagues conducted a multicenter, double-blind, parallel-group study to compare the efficacy and safety of arbaclofen ER with those of placebo and baclofen in patients with MS-related spasticity. They randomized adults in North America and Eastern Europe in equal groups to arbaclofen ER (20 mg b.i.d.), baclofen (20 mg q.i.d.), or placebo. The dose was titrated over 2 weeks, and participants subsequently entered a 12-week maintenance phase. The study’s two primary endpoints were the mean change in Total Numeric-Transformed Modified Ashworth Scale for the most affected limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) from baseline through the maintenance period.
Dr. Kantor and colleagues randomized 341 patients in their study. Of this population, 57.5% had relapsing-remitting MS, 38.4% had secondary progressive MS, 2.6% had primary progressive MS, and 0.9% had progressive relapsing MS. Thirteen patients from one site were excluded from analysis after study completion when an audit found irregularities. The mean baseline TNmAS-MAL score was 7.93 in the arbaclofen ER group, 7.75 in the baclofen group, and 7.55 in the placebo group. At the end of the maintenance period, the mean decrease in TNmAS-MAL score was larger with arbaclofen ER than with placebo (least-squares mean [LSMean] −2.90 vs. −1.95). In addition, CGIC was significantly improved for arbaclofen ER, compared with placebo (LSMean 1.00 vs. 0.52).
Furthermore, the change in MS Spasticity Scale (MSSS-88) was greater in the arbaclofen ER group than in the placebo group (−30.1 vs. −16.7). Results on the TNmAS, CGIC, and MSSS-88 did not significantly differ between arbaclofen ER and baclofen. Drowsiness and dizziness were less common in the arbaclofen ER group than in the baclofen group. A total of 63 (57.3%) patients receiving arbaclofen ER, 82 (72.6%) receiving baclofen, and 59 (50.0%) receiving placebo reported treatment-emergent adverse events. The most common adverse events were somnolence, asthenia, and muscle weakness.
The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.
REPORTING FROM CMSC 2019
Alemtuzumab provides greater reductions in serum NfL than interferon beta-1a
Seattle – (MS), according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. This finding is consistent with the superior clinical efficacy of alemtuzumab, compared with interferon beta-1a, seen in clinical trials, said the researchers. The clinical implications of alemtuzumab’s reduction of NfL levels remain to be clarified.
The CARE-MS I trial indicated that alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a over 2 years in treatment-naive patients with relapsing-remitting MS. Serum NfL level may indicate response to disease-modifying therapy.
Evis Havari, MSc, laboratory head of neuroimmunology immunomodulation at Sanofi in Framingham, Mass., and colleagues analyzed CARE-MS I data to determine the effect of alemtuzumab and subcutaneous interferon beta-1a on serum NfL over 2 years. The investigators also sought to compare participants’ serum NfL levels with the age-dependent median serum NfL levels in healthy controls, based on the approach described by Disanto et al. (Ann Neurol. 2017;81[6]:857-70).
In CARE-MS I, the investigators measured serum NfL with a single-molecule array. They used Generalized Additive Models of Location, Scale, and Shape to model serum NfL distribution in healthy controls and its association with age. They also derived age-dependent percentiles of serum NfL. CARE-MS I patients received 44 mcg of subcutaneous interferon beta-1a 3 times per week or 12 mg/day of alemtuzumab (a 5-day course at baseline and a 3-day course at 1 year). To obtain an age-independent measure of serum NfL, the researchers dichotomized samples into levels above or below the median. They used repeated logistic regression to estimate odds ratios (ORs).
The age range of participants in CARE-MS I was 18-53 years. Mean Expanded Disability Status Scale score was 2.0. In all, 354 participants received alemtuzumab, and 157 received interferon beta-1a.
Median serum NfL levels for healthy controls ranged from 12.0 pg/mL at 18 years of age to 27.1 pg/mL at 53 years. Median serum NfL levels were similar between the alemtuzumab and interferon beta-1a groups at baseline (31.7 pg/mL vs. 31.4 pg/mL). At 6 months after treatment, median serum NfL levels were significantly lower with alemtuzumab than with interferon beta-1a (17.2 pg/mL vs. 21.4 pg/mL). These levels remained significantly lower at month 24 in the alemtuzumab group (13.2 pg/mL vs. 18.7 pg/mL).
Significantly fewer patients in the alemtuzumab group had serum NfL levels higher than the age-dependent median in healthy controls at each post baseline time point, compared with the interferon beta-1a group (month 6: 46% vs. 65%; month 12: 38% vs. 53%; month 18: 31% vs. 44%; month 24: 28% vs. 53%). The odds for achieving serum NfL levels less than or equal to median levels for healthy controls were significantly greater for alemtuzumab than interferon beta-1a at month 6 (OR, 2.34), month 12 (OR, 1.81), month 18 (OR, 1.72), and month 24 (OR, 2.85).
Sanofi and Bayer HealthCare Pharmaceuticals supported the study. Several of the investigators are employees of Sanofi.
SOURCE: Havari E et al. CMSC 2019. Abstract NIB01.
Seattle – (MS), according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. This finding is consistent with the superior clinical efficacy of alemtuzumab, compared with interferon beta-1a, seen in clinical trials, said the researchers. The clinical implications of alemtuzumab’s reduction of NfL levels remain to be clarified.
The CARE-MS I trial indicated that alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a over 2 years in treatment-naive patients with relapsing-remitting MS. Serum NfL level may indicate response to disease-modifying therapy.
Evis Havari, MSc, laboratory head of neuroimmunology immunomodulation at Sanofi in Framingham, Mass., and colleagues analyzed CARE-MS I data to determine the effect of alemtuzumab and subcutaneous interferon beta-1a on serum NfL over 2 years. The investigators also sought to compare participants’ serum NfL levels with the age-dependent median serum NfL levels in healthy controls, based on the approach described by Disanto et al. (Ann Neurol. 2017;81[6]:857-70).
In CARE-MS I, the investigators measured serum NfL with a single-molecule array. They used Generalized Additive Models of Location, Scale, and Shape to model serum NfL distribution in healthy controls and its association with age. They also derived age-dependent percentiles of serum NfL. CARE-MS I patients received 44 mcg of subcutaneous interferon beta-1a 3 times per week or 12 mg/day of alemtuzumab (a 5-day course at baseline and a 3-day course at 1 year). To obtain an age-independent measure of serum NfL, the researchers dichotomized samples into levels above or below the median. They used repeated logistic regression to estimate odds ratios (ORs).
The age range of participants in CARE-MS I was 18-53 years. Mean Expanded Disability Status Scale score was 2.0. In all, 354 participants received alemtuzumab, and 157 received interferon beta-1a.
Median serum NfL levels for healthy controls ranged from 12.0 pg/mL at 18 years of age to 27.1 pg/mL at 53 years. Median serum NfL levels were similar between the alemtuzumab and interferon beta-1a groups at baseline (31.7 pg/mL vs. 31.4 pg/mL). At 6 months after treatment, median serum NfL levels were significantly lower with alemtuzumab than with interferon beta-1a (17.2 pg/mL vs. 21.4 pg/mL). These levels remained significantly lower at month 24 in the alemtuzumab group (13.2 pg/mL vs. 18.7 pg/mL).
Significantly fewer patients in the alemtuzumab group had serum NfL levels higher than the age-dependent median in healthy controls at each post baseline time point, compared with the interferon beta-1a group (month 6: 46% vs. 65%; month 12: 38% vs. 53%; month 18: 31% vs. 44%; month 24: 28% vs. 53%). The odds for achieving serum NfL levels less than or equal to median levels for healthy controls were significantly greater for alemtuzumab than interferon beta-1a at month 6 (OR, 2.34), month 12 (OR, 1.81), month 18 (OR, 1.72), and month 24 (OR, 2.85).
Sanofi and Bayer HealthCare Pharmaceuticals supported the study. Several of the investigators are employees of Sanofi.
SOURCE: Havari E et al. CMSC 2019. Abstract NIB01.
Seattle – (MS), according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. This finding is consistent with the superior clinical efficacy of alemtuzumab, compared with interferon beta-1a, seen in clinical trials, said the researchers. The clinical implications of alemtuzumab’s reduction of NfL levels remain to be clarified.
The CARE-MS I trial indicated that alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a over 2 years in treatment-naive patients with relapsing-remitting MS. Serum NfL level may indicate response to disease-modifying therapy.
Evis Havari, MSc, laboratory head of neuroimmunology immunomodulation at Sanofi in Framingham, Mass., and colleagues analyzed CARE-MS I data to determine the effect of alemtuzumab and subcutaneous interferon beta-1a on serum NfL over 2 years. The investigators also sought to compare participants’ serum NfL levels with the age-dependent median serum NfL levels in healthy controls, based on the approach described by Disanto et al. (Ann Neurol. 2017;81[6]:857-70).
In CARE-MS I, the investigators measured serum NfL with a single-molecule array. They used Generalized Additive Models of Location, Scale, and Shape to model serum NfL distribution in healthy controls and its association with age. They also derived age-dependent percentiles of serum NfL. CARE-MS I patients received 44 mcg of subcutaneous interferon beta-1a 3 times per week or 12 mg/day of alemtuzumab (a 5-day course at baseline and a 3-day course at 1 year). To obtain an age-independent measure of serum NfL, the researchers dichotomized samples into levels above or below the median. They used repeated logistic regression to estimate odds ratios (ORs).
The age range of participants in CARE-MS I was 18-53 years. Mean Expanded Disability Status Scale score was 2.0. In all, 354 participants received alemtuzumab, and 157 received interferon beta-1a.
Median serum NfL levels for healthy controls ranged from 12.0 pg/mL at 18 years of age to 27.1 pg/mL at 53 years. Median serum NfL levels were similar between the alemtuzumab and interferon beta-1a groups at baseline (31.7 pg/mL vs. 31.4 pg/mL). At 6 months after treatment, median serum NfL levels were significantly lower with alemtuzumab than with interferon beta-1a (17.2 pg/mL vs. 21.4 pg/mL). These levels remained significantly lower at month 24 in the alemtuzumab group (13.2 pg/mL vs. 18.7 pg/mL).
Significantly fewer patients in the alemtuzumab group had serum NfL levels higher than the age-dependent median in healthy controls at each post baseline time point, compared with the interferon beta-1a group (month 6: 46% vs. 65%; month 12: 38% vs. 53%; month 18: 31% vs. 44%; month 24: 28% vs. 53%). The odds for achieving serum NfL levels less than or equal to median levels for healthy controls were significantly greater for alemtuzumab than interferon beta-1a at month 6 (OR, 2.34), month 12 (OR, 1.81), month 18 (OR, 1.72), and month 24 (OR, 2.85).
Sanofi and Bayer HealthCare Pharmaceuticals supported the study. Several of the investigators are employees of Sanofi.
SOURCE: Havari E et al. CMSC 2019. Abstract NIB01.
REPORTING FROM CMSC 2019
Key clinical point: Compared with interferon beta-1a, alemtuzumab provides greater reduction of serum NfL level.
Major finding: At month 24, median serum NfL level was 13.2 pg/mL in the alemtuzumab group and 18.7 pg/mL in the interferon group.
Study details: A prospective, randomized study of 511 patients with relapsing-remitting MS.
Disclosures: Sanofi and Bayer HealthCare Pharmaceuticals supported the study. Several of the investigators are employees of Sanofi.
Source: Havari E et al. CMSC 2019. Abstract NIB01.