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FDA approves viltolarsen (Viltepso) for Duchenne muscular dystrophy
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
FDA expands Dysport use for cerebral palsy–related spasticity
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
First reported U.S. case of COVID-19 linked to Guillain-Barré syndrome
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
Huntington’s disease biomarkers appear 24 years before clinical symptoms
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
FROM LANCET NEUROLOGY
Dermatomyositis without dermatitis correlates with autoantibodies
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
FROM JAMA NEUROLOGY
First case of COVID-19 presenting as Guillain-Barré reported
The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.
The case study was published online April 1 in Lancet Neurology.
GBS presentation
The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.
At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.
A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.
Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.
She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.
The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.
At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
Different pattern from Zika
Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.
Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.
“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.
“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.
“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.
This article was first published on Medscape.com.
The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.
The case study was published online April 1 in Lancet Neurology.
GBS presentation
The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.
At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.
A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.
Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.
She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.
The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.
At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
Different pattern from Zika
Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.
Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.
“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.
“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.
“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.
This article was first published on Medscape.com.
The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.
The case study was published online April 1 in Lancet Neurology.
GBS presentation
The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.
At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.
A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.
Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.
She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.
The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.
At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
Different pattern from Zika
Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.
Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.
“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.
“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.
“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.
This article was first published on Medscape.com.
Expert says progress in gut-brain research requires an open mind
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
FROM GMFH 2020
As costs for neurologic drugs rise, adherence to therapy drops
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.
The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.
Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.
Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.
Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.
“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.
Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.
The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.
SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.
FROM NEUROLOGY
FDA approves Vyondys 53 for Duchenne muscular dystrophy subtype
The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.
Separately, the agency approved the first newborn screening test for DMD.
DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.
“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
A surrogate endpoint
The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.
A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.
The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.
Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
Newborn screening
On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.
The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.
DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.
The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.
PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.
Separately, the agency approved the first newborn screening test for DMD.
DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.
“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
A surrogate endpoint
The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.
A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.
The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.
Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
Newborn screening
On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.
The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.
DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.
The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.
PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.
Separately, the agency approved the first newborn screening test for DMD.
DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.
“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
A surrogate endpoint
The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.
A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.
The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.
Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
Newborn screening
On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.
The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.
DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.
The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.
PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
