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Salivary biomarker identified for Huntington’s disease
SAN DIEGO – Huntingtin protein – the key biomarker for Huntington’s disease – can be detected in saliva, which might prove to be an easy and inexpensive way to diagnose and monitor Huntington’s, and perhaps even predict clinical onset, according to investigators at the University of California, San Diego.
In a study of 178 subjects, they found that salivary total huntingtin protein (Htt) was significantly increased in saliva from individuals with Huntington’s disease (HD), compared with controls without HD (mean, 0.775 ng/mL vs. 0.359 ng/mL; P = .0012). Levels remained consistent throughout the day and from day to day, and were not affected by age or sex.
Meanwhile, salivary mutant Htt levels were higher in gene-positive, premanifest HD subjects than in normal controls (P less than .05). Salivary C-reactive protein level was also significantly elevated in premanifest HD subjects (9,548 pg/mL vs. 3,399 pg/mL, P = .025), indicating a pathologic inflammatory or metabolic state. When considered together, the two measurements might herald the onset of symptoms.
There’s an acute need for a convenient, inexpensive HD biomarker. Htt isn’t often measured in clinical practice, and when it is, it’s assessed from blood or cerebrospinal fluid. With salivary Htt, “you don’t need any specialized personnel, [and samples] are easy to obtain and process. They keep well and are very stable. We don’t have to rush to get them somewhere,” said lead investigator Jody Corey-Bloom, MD, PhD, professor emeritus of neurosciences at the university.
“We are really excited about the potential of salivary Htt. We think this is going to be an easy way to follow patients,” she said at the annual meeting of the American Neurological Association.
The next step is to see how salivary Htt correlates with cerebrospinal fluid and blood levels. The team will also investigate it as a diagnostic tool; perhaps there’s a cut point that diagnoses HD. “It’s an intriguing idea,” Dr. Corey-Bloom said.
Perhaps the greatest potential is for predicting disease onset so treatments can be started before symptoms emerge. There’s nothing on the market yet that can delay or prevent progression, but trials are in the works for therapeutics that lower levels of mutant Htt in the brain. “If we can use something simple like salivary Htt [to start preemptive treatment] that would be phenomenal. That’s the hope,” she said.
Subjects refrained from smoking, eating, drinking, and brushing their teeth for at least an hour before saliva samples were taken. Testing was done by Western blot and enzyme-linked immunosorbent assay.
The work was funded by the university. Dr. Corey-Bloom said she had no relevant disclosures.
SAN DIEGO – Huntingtin protein – the key biomarker for Huntington’s disease – can be detected in saliva, which might prove to be an easy and inexpensive way to diagnose and monitor Huntington’s, and perhaps even predict clinical onset, according to investigators at the University of California, San Diego.
In a study of 178 subjects, they found that salivary total huntingtin protein (Htt) was significantly increased in saliva from individuals with Huntington’s disease (HD), compared with controls without HD (mean, 0.775 ng/mL vs. 0.359 ng/mL; P = .0012). Levels remained consistent throughout the day and from day to day, and were not affected by age or sex.
Meanwhile, salivary mutant Htt levels were higher in gene-positive, premanifest HD subjects than in normal controls (P less than .05). Salivary C-reactive protein level was also significantly elevated in premanifest HD subjects (9,548 pg/mL vs. 3,399 pg/mL, P = .025), indicating a pathologic inflammatory or metabolic state. When considered together, the two measurements might herald the onset of symptoms.
There’s an acute need for a convenient, inexpensive HD biomarker. Htt isn’t often measured in clinical practice, and when it is, it’s assessed from blood or cerebrospinal fluid. With salivary Htt, “you don’t need any specialized personnel, [and samples] are easy to obtain and process. They keep well and are very stable. We don’t have to rush to get them somewhere,” said lead investigator Jody Corey-Bloom, MD, PhD, professor emeritus of neurosciences at the university.
“We are really excited about the potential of salivary Htt. We think this is going to be an easy way to follow patients,” she said at the annual meeting of the American Neurological Association.
The next step is to see how salivary Htt correlates with cerebrospinal fluid and blood levels. The team will also investigate it as a diagnostic tool; perhaps there’s a cut point that diagnoses HD. “It’s an intriguing idea,” Dr. Corey-Bloom said.
Perhaps the greatest potential is for predicting disease onset so treatments can be started before symptoms emerge. There’s nothing on the market yet that can delay or prevent progression, but trials are in the works for therapeutics that lower levels of mutant Htt in the brain. “If we can use something simple like salivary Htt [to start preemptive treatment] that would be phenomenal. That’s the hope,” she said.
Subjects refrained from smoking, eating, drinking, and brushing their teeth for at least an hour before saliva samples were taken. Testing was done by Western blot and enzyme-linked immunosorbent assay.
The work was funded by the university. Dr. Corey-Bloom said she had no relevant disclosures.
SAN DIEGO – Huntingtin protein – the key biomarker for Huntington’s disease – can be detected in saliva, which might prove to be an easy and inexpensive way to diagnose and monitor Huntington’s, and perhaps even predict clinical onset, according to investigators at the University of California, San Diego.
In a study of 178 subjects, they found that salivary total huntingtin protein (Htt) was significantly increased in saliva from individuals with Huntington’s disease (HD), compared with controls without HD (mean, 0.775 ng/mL vs. 0.359 ng/mL; P = .0012). Levels remained consistent throughout the day and from day to day, and were not affected by age or sex.
Meanwhile, salivary mutant Htt levels were higher in gene-positive, premanifest HD subjects than in normal controls (P less than .05). Salivary C-reactive protein level was also significantly elevated in premanifest HD subjects (9,548 pg/mL vs. 3,399 pg/mL, P = .025), indicating a pathologic inflammatory or metabolic state. When considered together, the two measurements might herald the onset of symptoms.
There’s an acute need for a convenient, inexpensive HD biomarker. Htt isn’t often measured in clinical practice, and when it is, it’s assessed from blood or cerebrospinal fluid. With salivary Htt, “you don’t need any specialized personnel, [and samples] are easy to obtain and process. They keep well and are very stable. We don’t have to rush to get them somewhere,” said lead investigator Jody Corey-Bloom, MD, PhD, professor emeritus of neurosciences at the university.
“We are really excited about the potential of salivary Htt. We think this is going to be an easy way to follow patients,” she said at the annual meeting of the American Neurological Association.
The next step is to see how salivary Htt correlates with cerebrospinal fluid and blood levels. The team will also investigate it as a diagnostic tool; perhaps there’s a cut point that diagnoses HD. “It’s an intriguing idea,” Dr. Corey-Bloom said.
Perhaps the greatest potential is for predicting disease onset so treatments can be started before symptoms emerge. There’s nothing on the market yet that can delay or prevent progression, but trials are in the works for therapeutics that lower levels of mutant Htt in the brain. “If we can use something simple like salivary Htt [to start preemptive treatment] that would be phenomenal. That’s the hope,” she said.
Subjects refrained from smoking, eating, drinking, and brushing their teeth for at least an hour before saliva samples were taken. Testing was done by Western blot and enzyme-linked immunosorbent assay.
The work was funded by the university. Dr. Corey-Bloom said she had no relevant disclosures.
AT ANA 2017
Key clinical point:
Major finding: Salivary total huntingtin protein was significantly increased in saliva from individuals with Huntington’s disease, compared with controls (mean, 0.775 ng/mL vs. 0.359 ng/mL, P = .0012).
Data source: Measurement of salivary Htt and other analytes in 178 subjects.
Disclosures: The work was funded by the University of California, San Diego. The lead investigator had no relevant financial disclosures.
Austedo approved for treatment of tardive dyskinesia
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of tardive dyskinesia in adults, according to an announcement from Teva Pharmaceutical Industries.
The agency’s approval of Austedo was based on results from two phase 3 clinical trials in which the drug was shown to be safe and effective at reducing involuntary movements collectively termed tardive dyskinesia, a debilitating and sometimes irreversible movement disorder which affects about 500,000 people in the United States. Austedo was first approved in April 2017 to treat chorea associated with Huntington’s disease.
“Physicians treating tardive dyskinesia will appreciate the therapy’s dosing flexibility and the ability to focus on directly treating the movement disorder and not disrupt the ongoing treatment for the underlying condition,” Michael Hayden, MD, PhD, President of Global R&D and Chief Scientific Officer at Teva, said in the announcement.
The full prescribing information can be viewed here.
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of tardive dyskinesia in adults, according to an announcement from Teva Pharmaceutical Industries.
The agency’s approval of Austedo was based on results from two phase 3 clinical trials in which the drug was shown to be safe and effective at reducing involuntary movements collectively termed tardive dyskinesia, a debilitating and sometimes irreversible movement disorder which affects about 500,000 people in the United States. Austedo was first approved in April 2017 to treat chorea associated with Huntington’s disease.
“Physicians treating tardive dyskinesia will appreciate the therapy’s dosing flexibility and the ability to focus on directly treating the movement disorder and not disrupt the ongoing treatment for the underlying condition,” Michael Hayden, MD, PhD, President of Global R&D and Chief Scientific Officer at Teva, said in the announcement.
The full prescribing information can be viewed here.
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of tardive dyskinesia in adults, according to an announcement from Teva Pharmaceutical Industries.
The agency’s approval of Austedo was based on results from two phase 3 clinical trials in which the drug was shown to be safe and effective at reducing involuntary movements collectively termed tardive dyskinesia, a debilitating and sometimes irreversible movement disorder which affects about 500,000 people in the United States. Austedo was first approved in April 2017 to treat chorea associated with Huntington’s disease.
“Physicians treating tardive dyskinesia will appreciate the therapy’s dosing flexibility and the ability to focus on directly treating the movement disorder and not disrupt the ongoing treatment for the underlying condition,” Michael Hayden, MD, PhD, President of Global R&D and Chief Scientific Officer at Teva, said in the announcement.
The full prescribing information can be viewed here.
FDA approves deutetrabenazine for Huntington’s-associated chorea
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of chorea associated with Huntington’s disease, according to an announcement by the drug’s manufacturer, Teva Pharmaceutical.
The random, sudden, involuntary twisting and writhing movements of chorea constitute perhaps the most striking symptom of Huntington’s disease and affect about 90% of the roughly 35,000 Americans with the fatal neurodegenerative disorder. Deutetrabenazine is only the second product approved to treat Huntington’s in any capacity, and it is the first in nearly a decade.
The most common side effects of deutetrabenazine were somnolence, diarrhea, dry mouth, and fatigue. Deutetrabenazine is contraindicated in patients with hepatic impairment; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; patients taking reserpine or within 20 days of discontinuing reserpine; and patients taking tetrabenazine. Deutetrabenazine can cause worsening of mood and is not recommended for suicidal patients or patients with improperly treated depression.
“Chorea associated with Huntington’s disease has a significant impact on those living with the disease and their families. The FDA’s approval of Austedo represents an important new treatment option for people with HD and highlights the need for more therapeutic resources for this underserved patient community,” Louise Vetter, CEO of the Huntington’s Disease Society of America, said in the company’s announcement.
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of chorea associated with Huntington’s disease, according to an announcement by the drug’s manufacturer, Teva Pharmaceutical.
The random, sudden, involuntary twisting and writhing movements of chorea constitute perhaps the most striking symptom of Huntington’s disease and affect about 90% of the roughly 35,000 Americans with the fatal neurodegenerative disorder. Deutetrabenazine is only the second product approved to treat Huntington’s in any capacity, and it is the first in nearly a decade.
The most common side effects of deutetrabenazine were somnolence, diarrhea, dry mouth, and fatigue. Deutetrabenazine is contraindicated in patients with hepatic impairment; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; patients taking reserpine or within 20 days of discontinuing reserpine; and patients taking tetrabenazine. Deutetrabenazine can cause worsening of mood and is not recommended for suicidal patients or patients with improperly treated depression.
“Chorea associated with Huntington’s disease has a significant impact on those living with the disease and their families. The FDA’s approval of Austedo represents an important new treatment option for people with HD and highlights the need for more therapeutic resources for this underserved patient community,” Louise Vetter, CEO of the Huntington’s Disease Society of America, said in the company’s announcement.
The Food and Drug Administration has approved deutetrabenazine (Austedo) for the treatment of chorea associated with Huntington’s disease, according to an announcement by the drug’s manufacturer, Teva Pharmaceutical.
The random, sudden, involuntary twisting and writhing movements of chorea constitute perhaps the most striking symptom of Huntington’s disease and affect about 90% of the roughly 35,000 Americans with the fatal neurodegenerative disorder. Deutetrabenazine is only the second product approved to treat Huntington’s in any capacity, and it is the first in nearly a decade.
The most common side effects of deutetrabenazine were somnolence, diarrhea, dry mouth, and fatigue. Deutetrabenazine is contraindicated in patients with hepatic impairment; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; patients taking reserpine or within 20 days of discontinuing reserpine; and patients taking tetrabenazine. Deutetrabenazine can cause worsening of mood and is not recommended for suicidal patients or patients with improperly treated depression.
“Chorea associated with Huntington’s disease has a significant impact on those living with the disease and their families. The FDA’s approval of Austedo represents an important new treatment option for people with HD and highlights the need for more therapeutic resources for this underserved patient community,” Louise Vetter, CEO of the Huntington’s Disease Society of America, said in the company’s announcement.
Intermediate alleles may confer mild, late-onset Huntington-like symptoms
Asymptomatic people who carry an intermediate number (27-35) of CAG repeats on the huntingtin gene – that is, the range just below the Huntington’s disease threshold of 36 CAG repeats – may be at increased risk for mild, late-onset symptoms, according to the first report to definitely associate intermediate alleles with such symptoms.
The prevalence of this distinct category of alleles for the huntingtin (HTT) gene, termed IA (for intermediate alleles), ranges from 1.5% to 5.8% both in the general population and in affected families. The clinical manifestations of Huntington’s disease associated with IAs have remain hidden until now in part because asymptomatic family members often decline to undergo genetic testing for the disorder and so are not identified as having IAs. Emerging evidence suggests that some people with IAs are more likely than those with a smaller number of CAG repeats to develop Huntington-like neuropathologic effects, but the data are sparse, and the question is controversial, said Esther Cubo, MD, PhD, of the department of neurology, Hospital Universitario Burgos (Spain) and her associates on behalf of the European Huntington’s Disease Network (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002944).
To examine this issue in a large cohort of at-risk individuals, the investigators assessed clinical and sociodemographic factors for 657 people enrolled in the European Huntington’s Disease Registry, which tracks the natural course of the disease in patients and family members treated in 1998 through 2014 at 140 medical centers in 17 European and 3 other countries. They focused on individuals who were asymptomatic at baseline: 76 (11.6%) men and women who had IAs (cases) and 581 (88.4%) who had fewer than 27 CAG repeats (controls). The two groups were similar in age, body mass index, educational background, socioeconomic status, tobacco and alcohol use, and medication use, and they scored similarly on measures of health-related quality of life, functional capacity, and the Unified Huntington’s Disease Rating Scale (UHDRS) for motor, behavioral, and cognitive status.
IA status was not associated with any significant differences between cases and controls who were younger than age 60. However, after age 60, participants with IAs had higher median total UHDRS motor scores (13.0 vs. 2.0) and were more likely to show mild gait abnormalities, chorea, and bradykinesia. In the small subgroup of patients who were followed longitudinally for up to 2 years, those with IAs showed faster cognitive decline over time; however, longer follow-up of larger groups of participants is needed to confirm this trend, the investigators said.
In addition, study participants with IAs reported lower quality of life and a greater degree of apathy than those without IAs, but these differences did not reach statistical significance. Whether apathy and poor quality of life reflect Huntington’s disease or simply correlate with normal aging could not be determined.
This study was limited by the relatively small number of participants with IAs, but the findings suggest that IAs “could produce a mild phenotype” of Huntington’s disease in some carriers after age 60. Alternatively, “clinical manifestations of Huntington’s disease in patents with IA might also be potentially accelerated by medical conditions, treatments, and environmental factors” associated with normal aging, Dr. Cubo and her associates added.
This study was supported by the European Huntington’s Disease Registry. Dr. Cubo reported receiving consulting fees from UCB, Allergan, and AbbVie.
These findings are limited by the study’s small cohort size and short follow-up, but they suggest that younger IA carriers will develop few if any signs of Huntington’s disease while older IA carriers may develop a very mild phenotype late in life.
Young IA carriers and carriers who have a low number of CAG repeats (fewer than 27) on the longer allele have “not too much to worry about.” Older IA carriers may develop some mild motor symptoms and a slightly faster cognitive decline as they age. All carriers should remain as fit and healthy as possible, as they have always been advised, and should look to their family members’ experiences as a good yardstick of what might happen to them.
Patrick J. Morrison, MD, DSc, is in the department of genetic medicine at Belfast HSC Trust and the Centre for Cancer Research and Cell Biology at Queens University of Belfast (Northern Ireland). Julián Benito-León, MD, PhD, is in the department of neurology at University Hospital “12 de Octubre” and in the department of medicine at Complutense University, both in Madrid. They reported no targeted funding for this work. Dr. Morrison and Dr. Benito-León made these remarks in an editorial accompanying Dr. Cubo’s report (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002958).
These findings are limited by the study’s small cohort size and short follow-up, but they suggest that younger IA carriers will develop few if any signs of Huntington’s disease while older IA carriers may develop a very mild phenotype late in life.
Young IA carriers and carriers who have a low number of CAG repeats (fewer than 27) on the longer allele have “not too much to worry about.” Older IA carriers may develop some mild motor symptoms and a slightly faster cognitive decline as they age. All carriers should remain as fit and healthy as possible, as they have always been advised, and should look to their family members’ experiences as a good yardstick of what might happen to them.
Patrick J. Morrison, MD, DSc, is in the department of genetic medicine at Belfast HSC Trust and the Centre for Cancer Research and Cell Biology at Queens University of Belfast (Northern Ireland). Julián Benito-León, MD, PhD, is in the department of neurology at University Hospital “12 de Octubre” and in the department of medicine at Complutense University, both in Madrid. They reported no targeted funding for this work. Dr. Morrison and Dr. Benito-León made these remarks in an editorial accompanying Dr. Cubo’s report (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002958).
These findings are limited by the study’s small cohort size and short follow-up, but they suggest that younger IA carriers will develop few if any signs of Huntington’s disease while older IA carriers may develop a very mild phenotype late in life.
Young IA carriers and carriers who have a low number of CAG repeats (fewer than 27) on the longer allele have “not too much to worry about.” Older IA carriers may develop some mild motor symptoms and a slightly faster cognitive decline as they age. All carriers should remain as fit and healthy as possible, as they have always been advised, and should look to their family members’ experiences as a good yardstick of what might happen to them.
Patrick J. Morrison, MD, DSc, is in the department of genetic medicine at Belfast HSC Trust and the Centre for Cancer Research and Cell Biology at Queens University of Belfast (Northern Ireland). Julián Benito-León, MD, PhD, is in the department of neurology at University Hospital “12 de Octubre” and in the department of medicine at Complutense University, both in Madrid. They reported no targeted funding for this work. Dr. Morrison and Dr. Benito-León made these remarks in an editorial accompanying Dr. Cubo’s report (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002958).
Asymptomatic people who carry an intermediate number (27-35) of CAG repeats on the huntingtin gene – that is, the range just below the Huntington’s disease threshold of 36 CAG repeats – may be at increased risk for mild, late-onset symptoms, according to the first report to definitely associate intermediate alleles with such symptoms.
The prevalence of this distinct category of alleles for the huntingtin (HTT) gene, termed IA (for intermediate alleles), ranges from 1.5% to 5.8% both in the general population and in affected families. The clinical manifestations of Huntington’s disease associated with IAs have remain hidden until now in part because asymptomatic family members often decline to undergo genetic testing for the disorder and so are not identified as having IAs. Emerging evidence suggests that some people with IAs are more likely than those with a smaller number of CAG repeats to develop Huntington-like neuropathologic effects, but the data are sparse, and the question is controversial, said Esther Cubo, MD, PhD, of the department of neurology, Hospital Universitario Burgos (Spain) and her associates on behalf of the European Huntington’s Disease Network (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002944).
To examine this issue in a large cohort of at-risk individuals, the investigators assessed clinical and sociodemographic factors for 657 people enrolled in the European Huntington’s Disease Registry, which tracks the natural course of the disease in patients and family members treated in 1998 through 2014 at 140 medical centers in 17 European and 3 other countries. They focused on individuals who were asymptomatic at baseline: 76 (11.6%) men and women who had IAs (cases) and 581 (88.4%) who had fewer than 27 CAG repeats (controls). The two groups were similar in age, body mass index, educational background, socioeconomic status, tobacco and alcohol use, and medication use, and they scored similarly on measures of health-related quality of life, functional capacity, and the Unified Huntington’s Disease Rating Scale (UHDRS) for motor, behavioral, and cognitive status.
IA status was not associated with any significant differences between cases and controls who were younger than age 60. However, after age 60, participants with IAs had higher median total UHDRS motor scores (13.0 vs. 2.0) and were more likely to show mild gait abnormalities, chorea, and bradykinesia. In the small subgroup of patients who were followed longitudinally for up to 2 years, those with IAs showed faster cognitive decline over time; however, longer follow-up of larger groups of participants is needed to confirm this trend, the investigators said.
In addition, study participants with IAs reported lower quality of life and a greater degree of apathy than those without IAs, but these differences did not reach statistical significance. Whether apathy and poor quality of life reflect Huntington’s disease or simply correlate with normal aging could not be determined.
This study was limited by the relatively small number of participants with IAs, but the findings suggest that IAs “could produce a mild phenotype” of Huntington’s disease in some carriers after age 60. Alternatively, “clinical manifestations of Huntington’s disease in patents with IA might also be potentially accelerated by medical conditions, treatments, and environmental factors” associated with normal aging, Dr. Cubo and her associates added.
This study was supported by the European Huntington’s Disease Registry. Dr. Cubo reported receiving consulting fees from UCB, Allergan, and AbbVie.
Asymptomatic people who carry an intermediate number (27-35) of CAG repeats on the huntingtin gene – that is, the range just below the Huntington’s disease threshold of 36 CAG repeats – may be at increased risk for mild, late-onset symptoms, according to the first report to definitely associate intermediate alleles with such symptoms.
The prevalence of this distinct category of alleles for the huntingtin (HTT) gene, termed IA (for intermediate alleles), ranges from 1.5% to 5.8% both in the general population and in affected families. The clinical manifestations of Huntington’s disease associated with IAs have remain hidden until now in part because asymptomatic family members often decline to undergo genetic testing for the disorder and so are not identified as having IAs. Emerging evidence suggests that some people with IAs are more likely than those with a smaller number of CAG repeats to develop Huntington-like neuropathologic effects, but the data are sparse, and the question is controversial, said Esther Cubo, MD, PhD, of the department of neurology, Hospital Universitario Burgos (Spain) and her associates on behalf of the European Huntington’s Disease Network (Neurology. 2016 Jul 8. doi: 10.1212/WNL.0000000000002944).
To examine this issue in a large cohort of at-risk individuals, the investigators assessed clinical and sociodemographic factors for 657 people enrolled in the European Huntington’s Disease Registry, which tracks the natural course of the disease in patients and family members treated in 1998 through 2014 at 140 medical centers in 17 European and 3 other countries. They focused on individuals who were asymptomatic at baseline: 76 (11.6%) men and women who had IAs (cases) and 581 (88.4%) who had fewer than 27 CAG repeats (controls). The two groups were similar in age, body mass index, educational background, socioeconomic status, tobacco and alcohol use, and medication use, and they scored similarly on measures of health-related quality of life, functional capacity, and the Unified Huntington’s Disease Rating Scale (UHDRS) for motor, behavioral, and cognitive status.
IA status was not associated with any significant differences between cases and controls who were younger than age 60. However, after age 60, participants with IAs had higher median total UHDRS motor scores (13.0 vs. 2.0) and were more likely to show mild gait abnormalities, chorea, and bradykinesia. In the small subgroup of patients who were followed longitudinally for up to 2 years, those with IAs showed faster cognitive decline over time; however, longer follow-up of larger groups of participants is needed to confirm this trend, the investigators said.
In addition, study participants with IAs reported lower quality of life and a greater degree of apathy than those without IAs, but these differences did not reach statistical significance. Whether apathy and poor quality of life reflect Huntington’s disease or simply correlate with normal aging could not be determined.
This study was limited by the relatively small number of participants with IAs, but the findings suggest that IAs “could produce a mild phenotype” of Huntington’s disease in some carriers after age 60. Alternatively, “clinical manifestations of Huntington’s disease in patents with IA might also be potentially accelerated by medical conditions, treatments, and environmental factors” associated with normal aging, Dr. Cubo and her associates added.
This study was supported by the European Huntington’s Disease Registry. Dr. Cubo reported receiving consulting fees from UCB, Allergan, and AbbVie.
FROM NEUROLOGY
Key clinical point: Asymptomatic people who carry an intermediate number (27-35) of CAG repeats on the huntingtin gene may be at increased risk for mild symptoms after age 60.
Major finding: After age 60, people with intermediate alleles had higher median UHDRS motor scores (13.0) than did people with fewer CAG repeats (2.0).
Data source: A retrospective, international, observational study involving 76 asymptomatic adults with 27-35 CAG repeats and 581 with fewer than 27 CAG repeats.
Disclosures: This study was supported by the European Huntington’s Disease Registry. Dr. Cubo reported receiving consulting fees from UCB, Allergan, and AbbVie.
Deutetrabenazine modestly reduces chorea of Huntington disease
A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.
First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”
The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”
Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.
The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).
The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.
Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.
Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.
“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.
The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.
The study demonstrated a proof of principle that deutetrabenazine, compared with placebo, provided improvement on chorea over 12 weeks and allowed less frequent drug dosing with fewer adverse effects, but it’s not possible to determine how the drug compares with tetrabenazine.
An ideal trial would involve three groups comparing deutetrabenazine, tetrabenazine, and placebo. A head-to-head, noninferiority comparison of deutetrabenazine against tetrabenazine, as was recommended by one of the developers of the compound, would also have been useful.
Nevertheless, tetrabenazine was approved by the FDA for the treatment of chorea in Huntington disease essentially based on efficacy data similar to the current study. Assuming deutetrabenazine was not priced significantly higher than tetrabenazine, its “favorable profile” would offer an additional option for patients and clinicians if and when the drug is approved.
The ongoing ARC-HD (Alternatives for Reducing Chorea in Huntington Disease) study is examining the safety and tolerability of patients with Huntington disease who switch from tetrabenazine to deutetrabenazine (and also includes patients from the current deutetrabenazine study who chose to switch to open-label deutetrabenazine). It should help to resolve whether the effect sizes are clinically meaningful and stable over a period longer than 12 weeks.
Michael D. Geschwind, MD, PhD, and Nick Paras, PhD, are in the department of neurology at the University of California, San Francisco. Dr. Geschwind reported receiving grants from the National Institute on Aging and from many sources in industry, including travel support from Teva. Dr. Paras reported receiving research support from Daiichi-Sankyo, the U.S. Department of Defense, and the Tau Consortium. Their comments are derived from an editorial accompanying the phase III trial’s paper (JAMA. 2016;316[1]:33-5).
The study demonstrated a proof of principle that deutetrabenazine, compared with placebo, provided improvement on chorea over 12 weeks and allowed less frequent drug dosing with fewer adverse effects, but it’s not possible to determine how the drug compares with tetrabenazine.
An ideal trial would involve three groups comparing deutetrabenazine, tetrabenazine, and placebo. A head-to-head, noninferiority comparison of deutetrabenazine against tetrabenazine, as was recommended by one of the developers of the compound, would also have been useful.
Nevertheless, tetrabenazine was approved by the FDA for the treatment of chorea in Huntington disease essentially based on efficacy data similar to the current study. Assuming deutetrabenazine was not priced significantly higher than tetrabenazine, its “favorable profile” would offer an additional option for patients and clinicians if and when the drug is approved.
The ongoing ARC-HD (Alternatives for Reducing Chorea in Huntington Disease) study is examining the safety and tolerability of patients with Huntington disease who switch from tetrabenazine to deutetrabenazine (and also includes patients from the current deutetrabenazine study who chose to switch to open-label deutetrabenazine). It should help to resolve whether the effect sizes are clinically meaningful and stable over a period longer than 12 weeks.
Michael D. Geschwind, MD, PhD, and Nick Paras, PhD, are in the department of neurology at the University of California, San Francisco. Dr. Geschwind reported receiving grants from the National Institute on Aging and from many sources in industry, including travel support from Teva. Dr. Paras reported receiving research support from Daiichi-Sankyo, the U.S. Department of Defense, and the Tau Consortium. Their comments are derived from an editorial accompanying the phase III trial’s paper (JAMA. 2016;316[1]:33-5).
The study demonstrated a proof of principle that deutetrabenazine, compared with placebo, provided improvement on chorea over 12 weeks and allowed less frequent drug dosing with fewer adverse effects, but it’s not possible to determine how the drug compares with tetrabenazine.
An ideal trial would involve three groups comparing deutetrabenazine, tetrabenazine, and placebo. A head-to-head, noninferiority comparison of deutetrabenazine against tetrabenazine, as was recommended by one of the developers of the compound, would also have been useful.
Nevertheless, tetrabenazine was approved by the FDA for the treatment of chorea in Huntington disease essentially based on efficacy data similar to the current study. Assuming deutetrabenazine was not priced significantly higher than tetrabenazine, its “favorable profile” would offer an additional option for patients and clinicians if and when the drug is approved.
The ongoing ARC-HD (Alternatives for Reducing Chorea in Huntington Disease) study is examining the safety and tolerability of patients with Huntington disease who switch from tetrabenazine to deutetrabenazine (and also includes patients from the current deutetrabenazine study who chose to switch to open-label deutetrabenazine). It should help to resolve whether the effect sizes are clinically meaningful and stable over a period longer than 12 weeks.
Michael D. Geschwind, MD, PhD, and Nick Paras, PhD, are in the department of neurology at the University of California, San Francisco. Dr. Geschwind reported receiving grants from the National Institute on Aging and from many sources in industry, including travel support from Teva. Dr. Paras reported receiving research support from Daiichi-Sankyo, the U.S. Department of Defense, and the Tau Consortium. Their comments are derived from an editorial accompanying the phase III trial’s paper (JAMA. 2016;316[1]:33-5).
A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.
First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”
The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”
Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.
The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).
The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.
Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.
Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.
“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.
The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.
A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.
First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”
The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile ... may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”
Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.
The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316[1]:40-50. doi: 10.1001/jama.2016.8655).
The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.
Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.
Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.
“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.
The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.
FROM JAMA
Key clinical point: Use of a deuterated form of tetrabenazine resulted in modest reductions in chorea of Huntington disease over 12 weeks, compared with placebo.
Major finding: The total maximal chorea score measured from baseline to maintenance therapy was reduced by a statistically significant 4.4 points in patients taking deutetrabenazine, compared with 1.9 point in those taking placebo.
Data source: A double-blind, randomized, placebo-controlled trial involving 90 patients genetically diagnosed with Huntington disease.
Disclosures: The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.