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Neurologists publish consensus statement on stridor in MSA
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.
MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.
The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.
Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.
Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.
During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.
The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.
FROM NEUROLOGY
Viral cause of acute flaccid myelitis eludes detection
A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.
Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.
A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm3 in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.
Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.
Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.
Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.
A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.
Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.
“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”
The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.
“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.
Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.
SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.
*Updated 10/14/2019.
A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.
Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.
A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm3 in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.
Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.
Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.
Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.
A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.
Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.
“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”
The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.
“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.
Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.
SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.
*Updated 10/14/2019.
A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.
Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.
A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm3 in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.
Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.
Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.
Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.
A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.
Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.
“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”
The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.
“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.
Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.
SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.
*Updated 10/14/2019.
FROM PEDIATRICS
Key clinical point: Acute flaccid myelitis shows a strong suggestion of viral etiology but a single causal virus is not identified.
Major finding: Patients with acute flaccid myelitis show infection with a range of viruses including enteroviruses.
Study details: A study of 305 cases of acute flaccid myelitis in the United States.
Disclosures: Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.
Source: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.
Coming soon!
Check back later this month for top news from the 2019 AANEM Annual Meeting in Austin.
Check back later this month for top news from the 2019 AANEM Annual Meeting in Austin.
Check back later this month for top news from the 2019 AANEM Annual Meeting in Austin.
Can a novel steroidal anti-inflammatory drug benefit patients with Duchenne muscular dystrophy?
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
Daily treatment with vamorolone at doses of 2.0 mg/kg per day and 6.0 mg/kg per day suggested possible efficacy in a 24-week study, researchers said. The exploratory study included 48 boys who had completed a phase 2a trial.
The treatment was safe and well tolerated, and patients who received 2.0 mg/kg per day had significantly improved muscle function, as assessed by time to stand, compared with natural history controls, according to the results, which were published in Neurology.
In addition, the novel drug may reduce “safety concerns typically seen with traditional glucocorticoids,” wrote Eric P. Hoffman, PhD, and coauthors. Dr. Hoffman is president and CEO of ReveraGen BioPharma in Rockville, Md., which is developing the drug, and associate dean for research in the school of pharmacy and pharmaceutical sciences at Binghamton (N.Y.) University.
In preclinical studies, vamorolone retained anti-inflammatory efficacy while reducing adverse effects, compared with prednisolone, in a manner that is “consistent with vamorolone blocking [nuclear factor-kappa beta]–associated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes,” the authors said.
Phase 1 and phase 2a studies suggest that the drug may have an improved safety profile. To assess possible efficacy and define optimal doses, the investigators conducted the 24-week extension study. Participants were boys aged 4 years to younger than 7 years who had never been treated with glucocorticoids. They received 0.25, 0.75, 2.0, or 6.0 mg/kg per day vamorolone in an oral suspension formulation. Twelve boys received each dose level.
“Vamorolone was well tolerated ... with no adverse events leading to reduction of drug dosing or withdrawal from the trial,” they said. “The [timed stand from supine] primary outcome measure in vamorolone-treated patients with DMD supports efficacy of the 2.0-mg/kg/d dose ... at 24 weeks,” they said. A secondary outcome measure, the 6-minute walk test, supports efficacy at this dose at 12 and 24 weeks of treatment.
Furthermore, the data indicate that the 2.0-mg/kg per day dose may be associated with less weight gain and improved bone turnover and insulin resistance biomarkers, relative to prednisone therapy. “There was evidence of adrenal suppression in a subset of boys with DMD treated with 2.0 mg/kg/d vamorolone, with 18% of patients showing reduced morning cortisol levels,” the authors said. “Future studies of vamorolone will include adrenocorticotropic hormone–challenge tests to further explore adrenal function.”
A double-blind, placebo-controlled trial of vamorolone is underway. Investigators are testing two doses of vamorolone (2.0 and 6.0 mg/kg per day) versus placebo and prednisone (0.75 mg/kg per day). Researchers plan to enroll 120 patients, with 30 patients in each arm.
ReveraGen BioPharma received funds for the present study from Actelion Pharmaceuticals, U.S. and European government agencies, and nonprofit foundations. Dr. Hoffman and some of his collaborators are cofounders of ReveraGen. Other coauthors received support from the company.
SOURCE: Hoffman EP et al. Neurology. 2019 Aug 26. doi: 10.1212/WNL.0000000000008168.
FROM NEUROLOGY
Peripheral nervous system events have lasting impact on SLE patients
Peripheral nervous system disease, predominantly neuropathies, constitutes a substantial proportion of the manifestations of neuropsychiatric systemic lupus erythematosus (SLE) and has a lasting negative impact on health-related quality of life, John G. Hanly, MD, of Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, N.S., and associates reported in Arthritis & Rheumatology.
According to the study of 1,827 SLE patients who had been recently diagnosed and enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network at sites in Europe, Asia, and North America during 1999-2011, 161 peripheral nervous system (PNS) events occurred in 139 of the patients (8%) over a mean 7.6 years of follow-up.
Using the seven American College of Rheumatology case definitions for PNS disease in neuropsychiatric SLE, most of the events were peripheral neuropathy (41%), mononeuropathy (27%), and cranial neuropathy (24%). For 110 with peripheral neuropathy or mononeuropathy who underwent electrophysiologic testing, axonal damage was often present (42%), followed by demyelination (22%).
The PNS events were attributed to SLE in about 58%-75% of the patients. Based on these data the investigators estimated that after 10 years the cumulative incidence of any PNS event regardless of its attribution was about 9%, and it was nearly 7% for events attributed to SLE.
The probability that the neuropathies would not resolve over time was estimated at about 43% for peripheral neuropathy, 29% for mononeuropathy, and 30% for cranial neuropathy. Resolution of neuropathy was most rapid for cranial neuropathy, followed by mononeuropathy and peripheral neuropathy.
Patients with PNS events had significantly lower physical and mental health component scores on the 36-item Short Form Health Survey than did patients without a neuropsychiatric event up to the study assessment, and these differences persisted for 10 years of follow-up.
These “findings provide a benchmark for the assessment of future treatment modalities,” the investigators concluded.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41070.
Peripheral nervous system disease, predominantly neuropathies, constitutes a substantial proportion of the manifestations of neuropsychiatric systemic lupus erythematosus (SLE) and has a lasting negative impact on health-related quality of life, John G. Hanly, MD, of Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, N.S., and associates reported in Arthritis & Rheumatology.
According to the study of 1,827 SLE patients who had been recently diagnosed and enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network at sites in Europe, Asia, and North America during 1999-2011, 161 peripheral nervous system (PNS) events occurred in 139 of the patients (8%) over a mean 7.6 years of follow-up.
Using the seven American College of Rheumatology case definitions for PNS disease in neuropsychiatric SLE, most of the events were peripheral neuropathy (41%), mononeuropathy (27%), and cranial neuropathy (24%). For 110 with peripheral neuropathy or mononeuropathy who underwent electrophysiologic testing, axonal damage was often present (42%), followed by demyelination (22%).
The PNS events were attributed to SLE in about 58%-75% of the patients. Based on these data the investigators estimated that after 10 years the cumulative incidence of any PNS event regardless of its attribution was about 9%, and it was nearly 7% for events attributed to SLE.
The probability that the neuropathies would not resolve over time was estimated at about 43% for peripheral neuropathy, 29% for mononeuropathy, and 30% for cranial neuropathy. Resolution of neuropathy was most rapid for cranial neuropathy, followed by mononeuropathy and peripheral neuropathy.
Patients with PNS events had significantly lower physical and mental health component scores on the 36-item Short Form Health Survey than did patients without a neuropsychiatric event up to the study assessment, and these differences persisted for 10 years of follow-up.
These “findings provide a benchmark for the assessment of future treatment modalities,” the investigators concluded.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41070.
Peripheral nervous system disease, predominantly neuropathies, constitutes a substantial proportion of the manifestations of neuropsychiatric systemic lupus erythematosus (SLE) and has a lasting negative impact on health-related quality of life, John G. Hanly, MD, of Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, N.S., and associates reported in Arthritis & Rheumatology.
According to the study of 1,827 SLE patients who had been recently diagnosed and enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network at sites in Europe, Asia, and North America during 1999-2011, 161 peripheral nervous system (PNS) events occurred in 139 of the patients (8%) over a mean 7.6 years of follow-up.
Using the seven American College of Rheumatology case definitions for PNS disease in neuropsychiatric SLE, most of the events were peripheral neuropathy (41%), mononeuropathy (27%), and cranial neuropathy (24%). For 110 with peripheral neuropathy or mononeuropathy who underwent electrophysiologic testing, axonal damage was often present (42%), followed by demyelination (22%).
The PNS events were attributed to SLE in about 58%-75% of the patients. Based on these data the investigators estimated that after 10 years the cumulative incidence of any PNS event regardless of its attribution was about 9%, and it was nearly 7% for events attributed to SLE.
The probability that the neuropathies would not resolve over time was estimated at about 43% for peripheral neuropathy, 29% for mononeuropathy, and 30% for cranial neuropathy. Resolution of neuropathy was most rapid for cranial neuropathy, followed by mononeuropathy and peripheral neuropathy.
Patients with PNS events had significantly lower physical and mental health component scores on the 36-item Short Form Health Survey than did patients without a neuropsychiatric event up to the study assessment, and these differences persisted for 10 years of follow-up.
These “findings provide a benchmark for the assessment of future treatment modalities,” the investigators concluded.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41070.
REPORTING FROM ARTHRITIS & RHEUMATOLOGY
NIH launches 5-year, $10 million study on acute flaccid myelitis
Researchers at the University of Alabama at Birmingham will lead a 5-year, federally-funded study of acute flaccid myelitis (AFM) – a rare pediatric neurologic disease.
The National Institute of Allergy and Infectious Diseases (NIAID) awarded the $10 million grant to primary investigator David Kimberlin, MD, a UAB professor of pediatrics. Carlos Pardo-Villamizar, MD, professor of neurology and pathology at Johns Hopkins University, Baltimore, is the co-principal investigator.
The university will organize and implement the international, multisite study. Its primary goal is to examine the incidence and distribution of AFM, and its pathogenesis and progression. Enrollment is expected to commence next fall. Investigators will enroll children with symptoms of AFM and follow them for 1 year. Household contacts of the subjects will serve as comparators.
In addition to collecting data about risk factors and disease progression, the researchers will collect clinical specimens, including blood and cerebrospinal fluid. More details about the design and study sites will be released then, according to a press statement issued by NIAID.
AFM targets spinal nerves and often develops after a mild respiratory illness. The disease mounted a global epidemic comeback in 2014, primarily affecting children; it has occurred concurrently with enterovirus outbreaks.
“Growing epidemiological evidence suggests that enterovirus-D68 [EV-D68] could play a role,” the statement noted. “Most people who become infected with EV-D68 are asymptomatic or experience mild, cold-like symptoms. Researchers and physicians are working to understand if there is a connection between these viral outbreaks and AFM, and if so, why some children but not others experience this sudden muscle weakness and paralysis.”
The study will draw on the expertise of the AFM Task Force, established last fall. The group comprises physicians, scientists, and public health experts from diverse disciplines and institutions who will assist in the ongoing investigation.
The AFM natural history study is funded under contract HHSN272201600018C.
Researchers at the University of Alabama at Birmingham will lead a 5-year, federally-funded study of acute flaccid myelitis (AFM) – a rare pediatric neurologic disease.
The National Institute of Allergy and Infectious Diseases (NIAID) awarded the $10 million grant to primary investigator David Kimberlin, MD, a UAB professor of pediatrics. Carlos Pardo-Villamizar, MD, professor of neurology and pathology at Johns Hopkins University, Baltimore, is the co-principal investigator.
The university will organize and implement the international, multisite study. Its primary goal is to examine the incidence and distribution of AFM, and its pathogenesis and progression. Enrollment is expected to commence next fall. Investigators will enroll children with symptoms of AFM and follow them for 1 year. Household contacts of the subjects will serve as comparators.
In addition to collecting data about risk factors and disease progression, the researchers will collect clinical specimens, including blood and cerebrospinal fluid. More details about the design and study sites will be released then, according to a press statement issued by NIAID.
AFM targets spinal nerves and often develops after a mild respiratory illness. The disease mounted a global epidemic comeback in 2014, primarily affecting children; it has occurred concurrently with enterovirus outbreaks.
“Growing epidemiological evidence suggests that enterovirus-D68 [EV-D68] could play a role,” the statement noted. “Most people who become infected with EV-D68 are asymptomatic or experience mild, cold-like symptoms. Researchers and physicians are working to understand if there is a connection between these viral outbreaks and AFM, and if so, why some children but not others experience this sudden muscle weakness and paralysis.”
The study will draw on the expertise of the AFM Task Force, established last fall. The group comprises physicians, scientists, and public health experts from diverse disciplines and institutions who will assist in the ongoing investigation.
The AFM natural history study is funded under contract HHSN272201600018C.
Researchers at the University of Alabama at Birmingham will lead a 5-year, federally-funded study of acute flaccid myelitis (AFM) – a rare pediatric neurologic disease.
The National Institute of Allergy and Infectious Diseases (NIAID) awarded the $10 million grant to primary investigator David Kimberlin, MD, a UAB professor of pediatrics. Carlos Pardo-Villamizar, MD, professor of neurology and pathology at Johns Hopkins University, Baltimore, is the co-principal investigator.
The university will organize and implement the international, multisite study. Its primary goal is to examine the incidence and distribution of AFM, and its pathogenesis and progression. Enrollment is expected to commence next fall. Investigators will enroll children with symptoms of AFM and follow them for 1 year. Household contacts of the subjects will serve as comparators.
In addition to collecting data about risk factors and disease progression, the researchers will collect clinical specimens, including blood and cerebrospinal fluid. More details about the design and study sites will be released then, according to a press statement issued by NIAID.
AFM targets spinal nerves and often develops after a mild respiratory illness. The disease mounted a global epidemic comeback in 2014, primarily affecting children; it has occurred concurrently with enterovirus outbreaks.
“Growing epidemiological evidence suggests that enterovirus-D68 [EV-D68] could play a role,” the statement noted. “Most people who become infected with EV-D68 are asymptomatic or experience mild, cold-like symptoms. Researchers and physicians are working to understand if there is a connection between these viral outbreaks and AFM, and if so, why some children but not others experience this sudden muscle weakness and paralysis.”
The study will draw on the expertise of the AFM Task Force, established last fall. The group comprises physicians, scientists, and public health experts from diverse disciplines and institutions who will assist in the ongoing investigation.
The AFM natural history study is funded under contract HHSN272201600018C.
Study refines ALS risk among first-degree relatives of patients with disease
, according to a recent Irish population–based study.
Among first-degree relatives of individuals with ALS whose genetic status was unknown, the lifetime risk of developing ALS was 1.4%, compared with 0.3% in the general population (P less than .001).
Overall, lifetime heritability for the 1,117 patients in the heritability study cohort was 52.3% (95% confidence interval, 42.9%-61.7%). The highest heritability was seen in mother-daughter dyads; here, the concordance rate for ALS was 2.6% and the heritability estimate was 66.2% (95% CI, 58.5%-73.9%), “pointing to a previously unrecognized sex-mediated association with disease heritability,” Marie Ryan, MD, and coauthors at Trinity College Dublin wrote in JAMA Neurology.
For the purposes of this study, heritability was defined as “the proportion of variance in liability that is attributable to additive genetic factors,” explained the investigators. Their model was applied to 1,123 Irish patients with incident ALS over a 10-year study period, drawing on a national database. Complete medical histories were available for both parents of every individual in the cohort, and the investigators identified 32 parent-offspring dyads with ALS.
In their assessment of “liability” for ALS, Dr. Ryan and colleagues accounted for age-specific and sex-specific ALS incidence rates, using a well-delineated United States reference population. They also took into account competing mortality risks that might intervene before an individual developed ALS.
Although mother-daughter dyads yielded the highest heritability estimates, heritability was also elevated among father-son dyads, at 50.1% (95% CI, 42.0%-59.4%). Opposite-sex dyads (mother-son and father-daughter) yielded similar, and lower, heritability estimates of 34%-38%. Dr. Ryan and coinvestigators acknowledged that female sex hormones might play a role in mediating risk for ALS, but the contribution and mechanism are currently unknown.
The investigators identified 674 patients in the cohort who had been tested for C9orf72; large repeat expansions in the GGGGCC segment of this gene are known to cause ALS. In all, 69 patients were C9orf72 positive, and 14 of these individuals (20.3%) reported that one parent had ALS. Among the entire cohort, 23 of the 32 patients with parents who also had ALS had C9orf72 testing, and 14 of 23 (60.9%) were positive. This discrepancy, wrote Dr. Ryan and coauthors, suggests that “genetic anticipation or pleiotropic effects may have masked the clinical phenotype in their parents.”
Parents were a mean 69.6 years old at the time of diagnosis, and offspring were a mean 52.0 years old; 56% of patients in the study cohort were male.
“[I]n our study, ALS heritability was assessed for the first time in a population in whom genetic mutations have been excluded,” wrote Dr. Ryan and coinvestigators. “We have found that, in the absence of known ALS-associated genetic mutations in the proband, first-degree relatives of individuals with ALS remain at increased risk of developing ALS compared with the general population.”
Dr. Ryan and one coauthor reported receiving funding from Science Foundation Ireland, and one coauthor reported receiving book royalties from Taylor & Francis, and fees from Cytokinetics and Wave Pharmaceuticals. The study was funded by Science Foundation Ireland and the Motor Neurone Disease Association.
SOURCE: Ryan M et al. JAMA Neurol. 2019 Jul 22. doi: 10.1001/jamaneurol.2019.2044.
, according to a recent Irish population–based study.
Among first-degree relatives of individuals with ALS whose genetic status was unknown, the lifetime risk of developing ALS was 1.4%, compared with 0.3% in the general population (P less than .001).
Overall, lifetime heritability for the 1,117 patients in the heritability study cohort was 52.3% (95% confidence interval, 42.9%-61.7%). The highest heritability was seen in mother-daughter dyads; here, the concordance rate for ALS was 2.6% and the heritability estimate was 66.2% (95% CI, 58.5%-73.9%), “pointing to a previously unrecognized sex-mediated association with disease heritability,” Marie Ryan, MD, and coauthors at Trinity College Dublin wrote in JAMA Neurology.
For the purposes of this study, heritability was defined as “the proportion of variance in liability that is attributable to additive genetic factors,” explained the investigators. Their model was applied to 1,123 Irish patients with incident ALS over a 10-year study period, drawing on a national database. Complete medical histories were available for both parents of every individual in the cohort, and the investigators identified 32 parent-offspring dyads with ALS.
In their assessment of “liability” for ALS, Dr. Ryan and colleagues accounted for age-specific and sex-specific ALS incidence rates, using a well-delineated United States reference population. They also took into account competing mortality risks that might intervene before an individual developed ALS.
Although mother-daughter dyads yielded the highest heritability estimates, heritability was also elevated among father-son dyads, at 50.1% (95% CI, 42.0%-59.4%). Opposite-sex dyads (mother-son and father-daughter) yielded similar, and lower, heritability estimates of 34%-38%. Dr. Ryan and coinvestigators acknowledged that female sex hormones might play a role in mediating risk for ALS, but the contribution and mechanism are currently unknown.
The investigators identified 674 patients in the cohort who had been tested for C9orf72; large repeat expansions in the GGGGCC segment of this gene are known to cause ALS. In all, 69 patients were C9orf72 positive, and 14 of these individuals (20.3%) reported that one parent had ALS. Among the entire cohort, 23 of the 32 patients with parents who also had ALS had C9orf72 testing, and 14 of 23 (60.9%) were positive. This discrepancy, wrote Dr. Ryan and coauthors, suggests that “genetic anticipation or pleiotropic effects may have masked the clinical phenotype in their parents.”
Parents were a mean 69.6 years old at the time of diagnosis, and offspring were a mean 52.0 years old; 56% of patients in the study cohort were male.
“[I]n our study, ALS heritability was assessed for the first time in a population in whom genetic mutations have been excluded,” wrote Dr. Ryan and coinvestigators. “We have found that, in the absence of known ALS-associated genetic mutations in the proband, first-degree relatives of individuals with ALS remain at increased risk of developing ALS compared with the general population.”
Dr. Ryan and one coauthor reported receiving funding from Science Foundation Ireland, and one coauthor reported receiving book royalties from Taylor & Francis, and fees from Cytokinetics and Wave Pharmaceuticals. The study was funded by Science Foundation Ireland and the Motor Neurone Disease Association.
SOURCE: Ryan M et al. JAMA Neurol. 2019 Jul 22. doi: 10.1001/jamaneurol.2019.2044.
, according to a recent Irish population–based study.
Among first-degree relatives of individuals with ALS whose genetic status was unknown, the lifetime risk of developing ALS was 1.4%, compared with 0.3% in the general population (P less than .001).
Overall, lifetime heritability for the 1,117 patients in the heritability study cohort was 52.3% (95% confidence interval, 42.9%-61.7%). The highest heritability was seen in mother-daughter dyads; here, the concordance rate for ALS was 2.6% and the heritability estimate was 66.2% (95% CI, 58.5%-73.9%), “pointing to a previously unrecognized sex-mediated association with disease heritability,” Marie Ryan, MD, and coauthors at Trinity College Dublin wrote in JAMA Neurology.
For the purposes of this study, heritability was defined as “the proportion of variance in liability that is attributable to additive genetic factors,” explained the investigators. Their model was applied to 1,123 Irish patients with incident ALS over a 10-year study period, drawing on a national database. Complete medical histories were available for both parents of every individual in the cohort, and the investigators identified 32 parent-offspring dyads with ALS.
In their assessment of “liability” for ALS, Dr. Ryan and colleagues accounted for age-specific and sex-specific ALS incidence rates, using a well-delineated United States reference population. They also took into account competing mortality risks that might intervene before an individual developed ALS.
Although mother-daughter dyads yielded the highest heritability estimates, heritability was also elevated among father-son dyads, at 50.1% (95% CI, 42.0%-59.4%). Opposite-sex dyads (mother-son and father-daughter) yielded similar, and lower, heritability estimates of 34%-38%. Dr. Ryan and coinvestigators acknowledged that female sex hormones might play a role in mediating risk for ALS, but the contribution and mechanism are currently unknown.
The investigators identified 674 patients in the cohort who had been tested for C9orf72; large repeat expansions in the GGGGCC segment of this gene are known to cause ALS. In all, 69 patients were C9orf72 positive, and 14 of these individuals (20.3%) reported that one parent had ALS. Among the entire cohort, 23 of the 32 patients with parents who also had ALS had C9orf72 testing, and 14 of 23 (60.9%) were positive. This discrepancy, wrote Dr. Ryan and coauthors, suggests that “genetic anticipation or pleiotropic effects may have masked the clinical phenotype in their parents.”
Parents were a mean 69.6 years old at the time of diagnosis, and offspring were a mean 52.0 years old; 56% of patients in the study cohort were male.
“[I]n our study, ALS heritability was assessed for the first time in a population in whom genetic mutations have been excluded,” wrote Dr. Ryan and coinvestigators. “We have found that, in the absence of known ALS-associated genetic mutations in the proband, first-degree relatives of individuals with ALS remain at increased risk of developing ALS compared with the general population.”
Dr. Ryan and one coauthor reported receiving funding from Science Foundation Ireland, and one coauthor reported receiving book royalties from Taylor & Francis, and fees from Cytokinetics and Wave Pharmaceuticals. The study was funded by Science Foundation Ireland and the Motor Neurone Disease Association.
SOURCE: Ryan M et al. JAMA Neurol. 2019 Jul 22. doi: 10.1001/jamaneurol.2019.2044.
FROM JAMA NEUROLOGY
Novel genetic therapy reduces key protein in Huntington’s disease
according to a study published in the New England Journal of Medicine.
Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTTRx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTTRx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.
For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTTRx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.
The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.
Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.
The median peak plasma concentrations of HTTRx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.
Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.
An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.
The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.
according to a study published in the New England Journal of Medicine.
Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTTRx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTTRx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.
For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTTRx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.
The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.
Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.
The median peak plasma concentrations of HTTRx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.
Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.
An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.
The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.
according to a study published in the New England Journal of Medicine.
Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTTRx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTTRx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.
For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTTRx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.
The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.
Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.
The median peak plasma concentrations of HTTRx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.
Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.
An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.
The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.
SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Mutant huntingtin and neurofilament light are potential biomarkers in Huntington’s disease
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.
Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.
To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.
The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.
Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.
When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.
Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.
All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.
In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).
Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”
The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.
This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
This article was updated 6/18/19.
SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.
REPORTING FROM AAN 2019
Key clinical point: Mutant huntingtin and plasma and cerebrospinal fluid levels of neurofilament light are useful potential biomarkers in Huntington’s disease.
Major finding: Levels of neurofilament light in plasma are correlated with those in cerebrospinal fluid.
Study details: A prospective, observational, longitudinal cohort study including 80 participants with and without Huntington’s disease.
Disclosures: This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
Source: Rodrigues FB et al. AAN 2019, Abstract S16.003.
Can an antisense oligonucleotide benefit patients with SOD1-ALS?
PHILADELPHIA – In patients with amyotrophic lateral sclerosis (ALS) caused by gain-of-toxic function mutations in the SOD1 gene, according to phase 1/2 trial results presented at the annual meeting of the American Academy of Neurology. Exploratory analyses suggest that the drug, known as tofersen (also known as BIIB067), may lessen declines in function, respiratory function, and strength. The treatment generally was safe and well tolerated, researchers said.
Most ALS cases are sporadic, but about 10% are genetic, of which approximately 20% are caused by SOD1 mutations. “Although SOD1-ALS disease progression is heterogeneous, the underlying pathophysiology, attributable to mutant SOD1 toxicity, is thought to be consistent across SOD1 mutation types,” said Timothy M. Miller, MD, PhD, of Washington University, St. Louis, and colleagues. “As such, effective reduction of SOD1 protein, irrespective of mutation, has the potential to alter the disease course of people with SOD1-ALS.”
Tofersen is an antisense oligonucleotide ribonuclease H1-mediated inhibitor of SOD1 messenger RNA. To study its safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy in patients with SOD1-ALS, investigators conducted a double-blind study. The investigators randomized 50 patients with ALS with a SOD1 mutation to 20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), or 100 mg (n = 10) of tofersen or placebo (n = 12).
Patients received tofersen by intrathecal bolus over 1-3 minutes. They received a loading regimen on days 1, 15, and 29 and maintenance dosing on days 57 and 85. After the dosing period, patients completed a 12-week follow-up period.
Adverse events
All patients received at least one dose of the study treatment, and 48 received all treatments. Three patients died during the study. One patient in the 20-mg group died of pulmonary embolism, and one patient in both the 60-mg group and placebo group died of respiratory failure. Investigators considered the deaths secondary to ALS or other conditions and not drug related.
Most adverse events were mild or moderate. The most common adverse events among tofersen-treated patients were headache (n = 16), procedural pain (n = 14), and post–lumbar puncture syndrome (n = 13). Five patients who received tofersen and two who received placebo experienced serious adverse events; no serious adverse events occurred in the 100-mg dose group.
“A reduction from baseline in CSF SOD1 concentrations was observed in the tofersen 40-, 60-, and 100-mg cohorts with the maximal reduction observed in the 100 mg–treated group [37% vs. no reduction in the placebo group; P less than 0.002] at day 85,” the investigators reported.
Possible efficacy
In exploratory analyses, the 100-mg dose slowed decline on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ASLFRS-R), compared with placebo. Mean change in ASLFRS-R from baseline to day 85 was –1.1 in patients who received 100 mg of tofersen, compared with –5.3 for patients who received placebo. Declines on measures of respiratory function and muscle strength also slowed. “Across clinical measures, separation from placebo was most apparent in participants with fast progressing disease,” the researchers said.
“Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord,” Dr. Miller said in a news release. “Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”
The study was sponsored by Biogen, which is developing tofersen. Some of the study authors are Biogen employees. Dr. Miller is on Biogen’s medical advisory board and receives clinical research support from Biogen. In addition, he consults, has licensing agreements with, and is a principal investigator for other companies.
PHILADELPHIA – In patients with amyotrophic lateral sclerosis (ALS) caused by gain-of-toxic function mutations in the SOD1 gene, according to phase 1/2 trial results presented at the annual meeting of the American Academy of Neurology. Exploratory analyses suggest that the drug, known as tofersen (also known as BIIB067), may lessen declines in function, respiratory function, and strength. The treatment generally was safe and well tolerated, researchers said.
Most ALS cases are sporadic, but about 10% are genetic, of which approximately 20% are caused by SOD1 mutations. “Although SOD1-ALS disease progression is heterogeneous, the underlying pathophysiology, attributable to mutant SOD1 toxicity, is thought to be consistent across SOD1 mutation types,” said Timothy M. Miller, MD, PhD, of Washington University, St. Louis, and colleagues. “As such, effective reduction of SOD1 protein, irrespective of mutation, has the potential to alter the disease course of people with SOD1-ALS.”
Tofersen is an antisense oligonucleotide ribonuclease H1-mediated inhibitor of SOD1 messenger RNA. To study its safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy in patients with SOD1-ALS, investigators conducted a double-blind study. The investigators randomized 50 patients with ALS with a SOD1 mutation to 20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), or 100 mg (n = 10) of tofersen or placebo (n = 12).
Patients received tofersen by intrathecal bolus over 1-3 minutes. They received a loading regimen on days 1, 15, and 29 and maintenance dosing on days 57 and 85. After the dosing period, patients completed a 12-week follow-up period.
Adverse events
All patients received at least one dose of the study treatment, and 48 received all treatments. Three patients died during the study. One patient in the 20-mg group died of pulmonary embolism, and one patient in both the 60-mg group and placebo group died of respiratory failure. Investigators considered the deaths secondary to ALS or other conditions and not drug related.
Most adverse events were mild or moderate. The most common adverse events among tofersen-treated patients were headache (n = 16), procedural pain (n = 14), and post–lumbar puncture syndrome (n = 13). Five patients who received tofersen and two who received placebo experienced serious adverse events; no serious adverse events occurred in the 100-mg dose group.
“A reduction from baseline in CSF SOD1 concentrations was observed in the tofersen 40-, 60-, and 100-mg cohorts with the maximal reduction observed in the 100 mg–treated group [37% vs. no reduction in the placebo group; P less than 0.002] at day 85,” the investigators reported.
Possible efficacy
In exploratory analyses, the 100-mg dose slowed decline on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ASLFRS-R), compared with placebo. Mean change in ASLFRS-R from baseline to day 85 was –1.1 in patients who received 100 mg of tofersen, compared with –5.3 for patients who received placebo. Declines on measures of respiratory function and muscle strength also slowed. “Across clinical measures, separation from placebo was most apparent in participants with fast progressing disease,” the researchers said.
“Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord,” Dr. Miller said in a news release. “Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”
The study was sponsored by Biogen, which is developing tofersen. Some of the study authors are Biogen employees. Dr. Miller is on Biogen’s medical advisory board and receives clinical research support from Biogen. In addition, he consults, has licensing agreements with, and is a principal investigator for other companies.
PHILADELPHIA – In patients with amyotrophic lateral sclerosis (ALS) caused by gain-of-toxic function mutations in the SOD1 gene, according to phase 1/2 trial results presented at the annual meeting of the American Academy of Neurology. Exploratory analyses suggest that the drug, known as tofersen (also known as BIIB067), may lessen declines in function, respiratory function, and strength. The treatment generally was safe and well tolerated, researchers said.
Most ALS cases are sporadic, but about 10% are genetic, of which approximately 20% are caused by SOD1 mutations. “Although SOD1-ALS disease progression is heterogeneous, the underlying pathophysiology, attributable to mutant SOD1 toxicity, is thought to be consistent across SOD1 mutation types,” said Timothy M. Miller, MD, PhD, of Washington University, St. Louis, and colleagues. “As such, effective reduction of SOD1 protein, irrespective of mutation, has the potential to alter the disease course of people with SOD1-ALS.”
Tofersen is an antisense oligonucleotide ribonuclease H1-mediated inhibitor of SOD1 messenger RNA. To study its safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy in patients with SOD1-ALS, investigators conducted a double-blind study. The investigators randomized 50 patients with ALS with a SOD1 mutation to 20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), or 100 mg (n = 10) of tofersen or placebo (n = 12).
Patients received tofersen by intrathecal bolus over 1-3 minutes. They received a loading regimen on days 1, 15, and 29 and maintenance dosing on days 57 and 85. After the dosing period, patients completed a 12-week follow-up period.
Adverse events
All patients received at least one dose of the study treatment, and 48 received all treatments. Three patients died during the study. One patient in the 20-mg group died of pulmonary embolism, and one patient in both the 60-mg group and placebo group died of respiratory failure. Investigators considered the deaths secondary to ALS or other conditions and not drug related.
Most adverse events were mild or moderate. The most common adverse events among tofersen-treated patients were headache (n = 16), procedural pain (n = 14), and post–lumbar puncture syndrome (n = 13). Five patients who received tofersen and two who received placebo experienced serious adverse events; no serious adverse events occurred in the 100-mg dose group.
“A reduction from baseline in CSF SOD1 concentrations was observed in the tofersen 40-, 60-, and 100-mg cohorts with the maximal reduction observed in the 100 mg–treated group [37% vs. no reduction in the placebo group; P less than 0.002] at day 85,” the investigators reported.
Possible efficacy
In exploratory analyses, the 100-mg dose slowed decline on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ASLFRS-R), compared with placebo. Mean change in ASLFRS-R from baseline to day 85 was –1.1 in patients who received 100 mg of tofersen, compared with –5.3 for patients who received placebo. Declines on measures of respiratory function and muscle strength also slowed. “Across clinical measures, separation from placebo was most apparent in participants with fast progressing disease,” the researchers said.
“Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord,” Dr. Miller said in a news release. “Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”
The study was sponsored by Biogen, which is developing tofersen. Some of the study authors are Biogen employees. Dr. Miller is on Biogen’s medical advisory board and receives clinical research support from Biogen. In addition, he consults, has licensing agreements with, and is a principal investigator for other companies.
REPORTING FROM AAN 2019