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Basal ganglia microcircuits offer clues to Parkinson’s symptoms
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
FROM NATURE NEUROSCIENCE
Neurologic disorders ubiquitous and rising in the U.S.
, according to new findings derived from the 2017 Global Burden of Disease study.
The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
Tracking the burden of neurologic diseases
Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.
The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.
The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.
Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
Regional variations
The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”
Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.
Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”
The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
Time to adjust the stroke belt?
Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia.
“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”
Dr. Boehme disclosed no financial conflicts of interest.
, according to new findings derived from the 2017 Global Burden of Disease study.
The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
Tracking the burden of neurologic diseases
Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.
The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.
The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.
Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
Regional variations
The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”
Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.
Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”
The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
Time to adjust the stroke belt?
Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia.
“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”
Dr. Boehme disclosed no financial conflicts of interest.
, according to new findings derived from the 2017 Global Burden of Disease study.
The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
Tracking the burden of neurologic diseases
Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.
The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.
The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.
Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
Regional variations
The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”
Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.
Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”
The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
Time to adjust the stroke belt?
Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia.
“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”
Dr. Boehme disclosed no financial conflicts of interest.
FROM JAMA NEUROLOGY
FDA approves first targeted treatment for rare DMD mutation
, the agency has announced.
This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.
“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
Approved – with cautions
The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.
As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.
The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.
The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.
Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.
Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.
Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.
Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.
However, it noted that definitive clinical benefits such as improved motor function were not “established.”
“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.
It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.
The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.
A version of this article first appeared on Medscape.com.
, the agency has announced.
This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.
“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
Approved – with cautions
The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.
As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.
The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.
The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.
Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.
Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.
Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.
Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.
However, it noted that definitive clinical benefits such as improved motor function were not “established.”
“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.
It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.
The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.
A version of this article first appeared on Medscape.com.
, the agency has announced.
This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.
“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
Approved – with cautions
The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.
As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.
The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.
The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.
Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.
Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.
Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.
Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.
However, it noted that definitive clinical benefits such as improved motor function were not “established.”
“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.
It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.
The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.
A version of this article first appeared on Medscape.com.
New steroid dosing regimen for myasthenia gravis
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.
Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.
“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.
The trial was published online Feb. 8 in JAMA Neurology.
Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.
The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.
They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.
Evaluating dosage regimens
To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.
In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.
In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.
First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.
Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.
Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.
Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.
In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.
Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.
The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).
Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.
The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.
The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).
The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.
They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.
“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.
The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
Particularly relevant to late-onset disease
Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.
Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding.
“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.
“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”
He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.
Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
Joint guidelines favor antibody testing for certain Lyme disease manifestations
New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.
The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.
This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.
“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
When to use and not to use PCR
Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.
Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.
To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.
“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”
Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.
Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”
If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.
Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.
They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.
The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.
Timelines for antibiotics
Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.
Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.
“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.
Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.
“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.
For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.
“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.
Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.
Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.
Advice on antibodies testing ‘particularly cogent’
For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.
“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.
The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.
The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.
SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.
New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.
The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.
This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.
“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
When to use and not to use PCR
Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.
Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.
To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.
“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”
Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.
Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”
If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.
Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.
They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.
The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.
Timelines for antibiotics
Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.
Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.
“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.
Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.
“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.
For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.
“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.
Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.
Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.
Advice on antibodies testing ‘particularly cogent’
For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.
“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.
The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.
The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.
SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.
New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.
The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.
This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.
“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
When to use and not to use PCR
Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.
Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.
To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.
“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”
Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.
Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”
If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.
Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.
They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.
The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.
Timelines for antibiotics
Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.
Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.
“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.
Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.
“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.
For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.
“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.
Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.
Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.
Advice on antibodies testing ‘particularly cogent’
For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.
“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.
The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.
The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.
SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.
FROM CLINICAL INFECTIOUS DISEASES
Gene-replacement therapy shows promise in X-linked myotubular myopathy
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
FROM CNS-ICNA 2020
Ataluren delays disease milestones in patients with nonsense mutation DMD
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
FROM CNS-ICNA 2020
Acute flaccid myelitis: More likely missed than diagnosed
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
FROM CNS-ICNA 2020
Nusinersen provides continued benefits to presymptomatic children with SMA
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
FROM CNS-ICNA 2020
Drug combo slows functional decline in ALS
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
From New England Journal of Medicine