US20160287574A1 - Methods for the treatment of abnormal involuntary movement disorders - Google Patents

Methods for the treatment of abnormal involuntary movement disorders Download PDF

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US20160287574A1
US20160287574A1 US15/063,068 US201615063068A US2016287574A1 US 20160287574 A1 US20160287574 A1 US 20160287574A1 US 201615063068 A US201615063068 A US 201615063068A US 2016287574 A1 US2016287574 A1 US 2016287574A1
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dose
certain embodiments
deutetrabenazine
daily amount
subject
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David Stamler
Michael Fangching HUANG
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Auspex Pharmaceuticals Inc
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Assigned to AUSPEX PHARMACEUTICALS, INC. reassignment AUSPEX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HUANG, Michael Fangching, STAMLER, David
Publication of US20160287574A1 publication Critical patent/US20160287574A1/en
Priority to US15/428,868 priority patent/US20170151227A1/en
Priority to US15/667,483 priority patent/US11648244B2/en
Priority to US15/722,208 priority patent/US11564917B2/en
Priority to US16/040,012 priority patent/US10959996B2/en
Assigned to AUSPEX PHARMACEUTICALS, INC. reassignment AUSPEX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STAMLER, David
Assigned to AUSPEX PHARMACEUTICALS, INC. reassignment AUSPEX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STAMLER, DAVID ALLEN
Priority to US17/154,312 priority patent/US11357772B2/en
Assigned to AUSPEX PHARMACEUTICALS, INC. reassignment AUSPEX PHARMACEUTICALS, INC. CHANGE OF ASSIGNEE ADDRESS Assignors: AUSPEX PHARMACEUTICALS, INC.
Priority to US17/212,205 priority patent/US11446291B2/en
Priority to US17/400,194 priority patent/US12016858B2/en
Priority to US18/677,401 priority patent/US20240316035A1/en
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Definitions

  • Movement disorders are neurological conditions that affect the speed, fluency, quality, and ease of movement. Movement disorders can be classified into two basic categories: those characterized by disordered or excessive movement (referred to as “dyskinesia” and “hyperkinesia” or “hyperkinetic movement disorders,” respectively), and those that are characterized by slowness, or a lack of movement (referred to as “hypokinesia,” “bradykinesia,” or “akinesia”).
  • An example of a “hyperkinetic” movement disorder is chorea, such as that associated with Huntington's disease (HD), while Parkinson's disease (PD) can be classified as “hypokinetic,” because it is often characterized by slow, deliberate movements, or even freezing in place. Both hyperkinetic and hypokinetic movement disorders can severely affect a subject's quality of life, making daily tasks difficult. Additionally, movement disorders can cause a subject physical pain and increase the probability of accidents.
  • chorea is an abnormal, involuntary, sudden movement that can affect all muscle groups and flow randomly from one body region to another; like many abnormal involuntary movements, it is often alternatively referred to as a movement disorder.
  • Chorea is a hallmark of Huntington's Disease. In the United States, an estimated 30,000 people have Huntington's disease. As many as 90% of patients with HD experience chorea and it is moderate to severe in approximately 70% of these patients. It is considered by clinicians to be a serious condition, given its significant interference with daily functioning and increased risk for injury to the patient. In its early stages, chorea can contribute to impaired speaking, writing, and activities of daily living such as feeding, dressing, and bathing.
  • chorea In its later stages, chorea can cause gait instability and poor postural control, with an increased risk of serious injury from falling or from flailing into objects. Severity of chorea and parkinsonism has been shown to be independently associated with falls in later-stage patients with HD. Dysphagia is a component of HD and can lead to recurrent aspiration pneumonia, weight loss, and behavioral problems.
  • tetrabenazine (XENAZINE®), an inhibitor of VMAT2. Tetrabenazine reduces presynaptic concentrations of monoamines, such as dopamine, in neurons that regulate body movements. Although approximately 30,000 people in the United States are affected by HD and approximately 200,000 individuals may carry the gene and be at risk of developing HD, according to a November 2013 presentation by Lundbeck, only approximately 4,000 patients received this therapy. A substantial majority of patients with chorea of HD are not receiving treatment with tetrabenazine.
  • UHDRS Unified Huntington's Disease Rating Scale
  • TMS Total Motor Score
  • All currently recruiting large Phase 2b/3 randomized clinical trials in patients with HD in the United States are using UHDRS-TMS as their primary endpoint.
  • Significant correlations between the UHDRS-TMS and functional measures for sleep, rest, eating, work, recreation and past-times, ambulation, mobility, body care and movement, social interaction, communication, physical, and psychosocial dimensions have been shown in patients with HD.
  • UHDRS-TMS scores are associated with a statistically significant lower likelihood of performing work, managing finances, driving safely, supervising children, and volunteering. Every 1-point worsening in the TMS was associated a 5% to 10% reduction in the likelihood of being able to complete these certain tasks.
  • the UHDRS-TMS is an independent predictor of functional disability based on scales including the 36-Item Short-Form Health Survey (SF-36).
  • Tardive dyskinesia is a hyperkinetic movement disorder that typically manifests as rapid, repetitive, stereotypic movements that can be induced by certain drugs, such as neuroleptics, such as dopamine receptor blocking agents, which are used for treating psychiatric conditions, as well as by drugs such as metoclopramide, which are used for treating various gastrointestinal disorders.
  • drugs such as neuroleptics, such as dopamine receptor blocking agents, which are used for treating psychiatric conditions, as well as by drugs such as metoclopramide, which are used for treating various gastrointestinal disorders.
  • compositions, dosing regimens, and methods for the treatment of abnormal muscular activity, abnormal involuntary movement and other related disorders are provided.
  • FIG. 1 shows change in mean chorea score observed in patients taking either deutetrabenazine or placebo from the First-HD study.
  • FIG. 2 presents the mean change from baseline in swallowing disturbance over time for deutetrabenazine and placebo (as determined by questionnaire), demonstrating a significant improvement in swallowing with deutetrabenazine treatment.
  • FIG. 3 presents the mean change from baseline in body weight (kg) over time for deutetrabenazine and placebo from the First-HD study.
  • FIG. 4 shows the mean total behavior score (A), anxiety (B) and compulsive behavior (C) for deutetrabenazine-treated subjects compared with the placebo group, from the First-HD study.
  • FIG. 5 shows change in mean chorea score observed in patients switched from tetrabenazine to deutetrabenazine, and the mean daily dose of tetrabenazine or deutetrabenazine corresponding to the chorea score, from the ARC-HD study.
  • FIG. 6 shows change in mean total motor score observed in patients switched from tetrabenazine to deutetrabenazine from the ARC-HD study.
  • FIG. 7 presents the mean change from baseline in swallowing disturbance over time in patients switched from tetrabenazine to deutetrabenazine (as determined by questionnaire) from the ARC-HD study, demonstrating a trend toward improvement in swallowing with deutetrabenazine treatment.
  • FIG. 8 shows the open-label long-term data in tardive dyskinesia patients from a tardive dyskinesia study as percent of treated subjects who were much improved or very much improved on a seven-point Likert scale of Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC).
  • PGIC Patient Global Impression of Change
  • CGIC Clinical Global Impression of Change
  • FIG. 9 shows the mean change in motor, vocal, and combined total tic scores in subjects treated in the pilot Tourette Syndrome study, from baseline through the end of treatment at week 8 and washout at week 9.
  • the top line (triangles) represents the vocal tic score; the middle line represents motor (squares) tic score, and the bottom line (diamonds) represents the total (combined motor and vocal) tic score.
  • Treatment with deutetrabenazine lowered (improved) both motor and vocal tics.
  • FIG. 10 shows the change in the Tourette Syndrome Clinical Global Impression in subjects treated in the pilot Tourette Syndrome study, from baseline through week 8; improvement is measured by reduction in TS-CGI score.
  • FIG. 11 shows the Tourette Syndrome Patient Global Impression of Change in subjects treated in the pilot Tourette Syndrome study, at week 8; improvement is measured by positive increase in TS-PGIC score wherein, e.g., 1 indicates minimally improved; 2, much improved; and 3, very much improved.
  • a method of treating abnormal involuntary movement in a subject comprising:
  • the abnormal involuntary movement is caused by a movement disorder.
  • the movement disorder is chosen from akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal), dystonia (general, segmental, or focal) including blepharospasm, writer's cramp (limb dystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibular dystonia, essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's Disease, multiple system atrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease levodopa-induced dyskinesia, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis (cervical dystonia), spasticity due to stroke
  • the movement disorder is a hyperkinetic movement disorder.
  • the abnormal involuntary movement is chosen from chorea, akathisia, dyskinesia, tremor, and tic.
  • the abnormal involuntary movement is chorea. In certain embodiments, the abnormal involuntary movement is chorea associated with Huntington's disease. In certain embodiments, the abnormal involuntary movement is a tic. In certain embodiments, the abnormal involuntary movement is a tic associated with Tourette syndrome.
  • movement disorder is chosen from Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, dystonia, and Parkinson's disease levodopa-induced dyskinesia.
  • the movement disorder is chosen from Huntington's disease, tardive dyskinesia, and Tourette syndrome.
  • the movement disorder is Huntington's disease.
  • the movement disorder is chorea associated with Huntington's disease.
  • the absence of a reduction or suspension in an initial or subsequent daily amount indicates that the daily amount is tolerable.
  • the tolerability is determined by assessment of one or more of the subject's levels of depression, anxiety, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, irritability, akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting and nausea.
  • a dose is not tolerated if one or more of the foregoing occur.
  • a dose is not tolerated if somnolence or dizziness occur.
  • the deuterium substituted tetrabenazine is deutetrabenazine.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine.
  • the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the VMAT2 inhibitor is a plus isomeric form of tetrabenazine.
  • the plus isomeric form of tetrabenazine is an alpha isomer.
  • the initial daily amount of deutetrabenazine is about 30% to about 70% of an existing total daily amount of tetrabenazine that provides adequate control of the abnormal involuntary movement. In certain embodiments, the initial daily amount of deutetrabenazine is about 40% to about 60% of an existing total daily amount of tetrabenazine that provides adequate control of the abnormal involuntary movement. In certain embodiments, the initial daily amount of deutetrabenazine is about 45% to about 55% of an existing total daily amount of tetrabenazine that provides adequate control of the abnormal involuntary movement. In certain embodiments, the initial daily amount of deutetrabenazine is about 30% to about 50% of an existing total daily amount of tetrabenazine that provides adequate control of the abnormal involuntary movement.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the initial daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for a subject concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the degree of chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved. In certain embodiments, motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS). In certain embodiments, the reduction in TMS score is at least 2 points. In certain embodiments, the reduction in TMS score is at least 3 points. In certain embodiments, the reduction in TMS score is at least 4 points.
  • TMS Total Motor Score
  • dystonia is improved.
  • gait is improved.
  • postural instability is alleviated.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen balance. In certain embodiments, the treatment improves balance.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant symptoms of parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [023]-[054] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • two embodiments are “mutually exclusive” when one is defined to be something which cannot overlap with the other.
  • deutetrabenazine for treating abnormal involuntary movement in a subject, as set forth herein or in any of the embodiments above in paragraphs [023]-[054] above.
  • deutetrabenazine in the manufacture of a medicament for treating abnormal involuntary movement in a subject as set forth herein or in any of the embodiments above in paragraphs [023]-[054] above.
  • a composition comprising deutetrabenazine for treating abnormal involuntary movement in a subject, as set forth herein or in any of the embodiments above in paragraphs [023]-[054] above.
  • the initial daily amount of deutetrabenazine is about 40% to about 60% of the existing total daily amount of tetrabenazine and is at least about 6 mg per day. In certain embodiments, the initial daily amount of deutetrabenazine is about 45% to about 55% of the existing total daily amount of tetrabenazine and is at least about 6 mg per day. In certain embodiments, the initial daily amount of deutetrabenazine is about 30% to about 50% of the existing total daily amount of tetrabenazine and is at least about 6 mg per day.
  • the abnormal involuntary movement is caused by a movement disorder.
  • the movement disorder is chosen from akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal), dystonia (general, segmental, or focal) including blepharospasm, writer's cramp (limb dystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibular dystonia, essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's Disease, multiple system atrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease levodopa-induced dyskinesia, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis (cervical dystonia), spasticity due to stroke
  • the movement disorder is a hyperkinetic movement disorder.
  • the abnormal involuntary movement is chosen from chorea, akathisia, dyskinesia, tremor, and tic.
  • the abnormal involuntary movement is chorea. In certain embodiments, the abnormal involuntary movement is chorea associated with Huntington's disease. In certain embodiments, the abnormal involuntary movement is a tic. In certain embodiments, the abnormal involuntary movement is a tic associated with Tourette syndrome.
  • movement disorder is chosen from Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, dystonia, and Parkinson's disease levodopa-induced dyskinesia.
  • the movement disorder is chosen from Huntington's disease, tardive dyskinesia, and Tourette syndrome.
  • the movement disorder is Huntington's disease.
  • the movement disorder is chorea associated with Huntington's disease.
  • the absence of a reduction or suspension in an initial or subsequent daily amount indicates that the daily amount is tolerable.
  • the tolerability is determined by assessment of one or more of the subject's levels of depression, anxiety, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, irritability, akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting and nausea.
  • a dose is not tolerated if one or more of the foregoing occur.
  • a dose is not tolerated if somnolence or dizziness occur.
  • the deuterium substituted tetrabenazine is deutetrabenazine.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine.
  • the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the VMAT2 inhibitor is a plus isomeric form of tetrabenazine.
  • the plus isomeric form of tetrabenazine is an alpha isomer.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. In certain embodiments, the daily amount of deutetrabenazine is about 6 mg to about 78 mg.
  • the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the initial daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. is improved. In certain embodiments, gait is improved. In certain embodiments, postural least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved.
  • motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS).
  • TMS Total Motor Score
  • the reduction in TMS score is at least 2 points.
  • the reduction in TMS score is at least 3 points.
  • the reduction in TMS score is at least 4 points.
  • dystonia is improved.
  • gait is improved.
  • postural instability is alleviated.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen the subject's balance. In certain embodiments, the treatment improves balance.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [056]-[090] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine for transitioning a subject receiving an existing total daily amount of tetrabenazine for control of abnormal involuntary movement, as set forth herein or in any of the embodiments above in paragraphs [056]-[090] above.
  • deutetrabenazine in the manufacture of a medicament for transitioning a subject receiving an existing total daily amount of tetrabenazine for control of abnormal involuntary movement, as set forth herein or in any of the embodiments above in paragraphs [056]-[090] above.
  • a composition comprising deutetrabenazine for use in transitioning a subject receiving an existing total daily amount of tetrabenazine for control of abnormal involuntary movement, as set forth herein or in any of the embodiments above in paragraphs [056]-[090] above.
  • Also provided is a method of treating a movement disorder in a subject comprising the administration of a daily amount of a VMAT2 inhibitor, wherein either:
  • chorea is reduced by at least 10% and any one or more of the following are true:
  • the movement disorder is chosen from akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal), dystonia (general, segmental, or focal) including blepharospasm, writer's cramp (limb dystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibular dystonia, essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's Disease, multiple system atrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease levodopa-induced dyskinesia, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis (cervical dystonia), spasticity due to stroke
  • the movement disorder is a hyperkinetic movement disorder.
  • dystonia is improved.
  • gait is improved.
  • postural instability is alleviated.
  • treatment reduces the symptoms of parkinsonism.
  • the movement disorder is chosen from Huntington's disease, tardive dyskinesia, and tics associated with Tourette syndrome.
  • the movement disorder is Huntington's disease. In certain embodiments, the movement disorder is chorea associated with Huntington's disease.
  • the movement disorder is a tic. In certain embodiments, the movement disorder is a tic associated with Tourette syndrome.
  • the VMAT2 inhibitor is a deuterium substituted tetrabenazine. In certain embodiments, the deuterium substituted tetrabenazine is deutetrabenazine. In certain embodiments, the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In certain embodiments, the plus isomeric form of tetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is valbenazine.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved.
  • motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS).
  • TMS Total Motor Score
  • the reduction in TMS score is at least 2 points.
  • the reduction in TMS score is at least 3 points.
  • the reduction in TMS score is at least 4 points.
  • dystonia is improved.
  • gait is improved.
  • postural instability is improved.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen the subject's balance. In certain embodiments, the treatment improves balance.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • chorea is reduced by at least 10% and any two or more of the following are true:
  • any embodiment above in paragraphs [092]-[0120] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • a VMAT2 inhibitor for treating a movement disorder in a subject as set forth herein or in any of the embodiments above in paragraphs [092]-[0120] above.
  • a VMAT2 inhibitor in the manufacture of a medicament for treating a movement disorder in a subject as set forth herein or in any of the embodiments above in paragraphs [092]-[0120] above.
  • a composition comprising a VMAT2 inhibitor for use in treating a movement disorder in a subject, as set forth herein or in any of the embodiments above in paragraphs [092]-[0120] above.
  • Also provided is a method of treating abnormal involuntary movement in a subject comprising administering an initial daily amount of a VMAT2 inhibitor to the subject, in a manner that:
  • the method comprises the additional steps of:
  • the method comprises the additional steps of:
  • the abnormal involuntary movement is a caused by a movement disorder.
  • the movement disorder is chosen from chorea associated with Huntington's disease, tardive dyskinesia, a tic associated with Tourette syndrome, dystonia, and Parkinson's disease levodopa-induced dyskinesia.
  • the movement disorder is chosen from chorea associated with Huntington's disease, tardive dyskinesia, and tics associated with Tourette syndrome.
  • the movement disorder is chorea associated with Huntington's disease.
  • the abnormal muscular activity is a tic. In certain embodiments, the abnormal muscular activity is a tic associated with Tourette syndrome.
  • the daily amount of deutetrabenazine improves one or more of the subject's symptoms of anxiety, swallowing, body weight, irritability, overall behavior, and compulsive behavior.
  • the movement disorder is chorea associated with Huntington's disease, and the daily amount of deutetrabenazine improves one or more of the subject's symptoms of depression, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, akathisia, parkinsonism, nausea, anxiety, impaired swallowing, body weight gain, irritability, and compulsive behavior.
  • the movement disorder is chosen from tardive dyskinesia and Tourette syndrome, and the daily amount of deutetrabenazine improves one or more of the subject's symptoms of depression, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, akathisia, parkinsonism, nausea, anxiety, impaired swallowing, irritability, and compulsive behavior.
  • the absence of a reduction or suspension in an initial or subsequent daily amount indicates that the daily amount is tolerable.
  • the tolerability is determined by assessment of one or more of the subject's levels of depression, anxiety, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, irritability, akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting and nausea.
  • a dose is not tolerated if one or more of the foregoing occur.
  • a dose is not tolerated if somnolence or dizziness occur.
  • the VMAT2 inhibitor is a deuterium substituted tetrabenazine. In certain embodiments, the deuterium substituted tetrabenazine is deutetrabenazine. In certain embodiments, the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In certain embodiments, the plus isomeric form of tetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is valbenazine.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the initial daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the initial daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved.
  • motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS).
  • TMS Total Motor Score
  • the reduction in TMS score is at least 2 points.
  • the reduction in TMS score is at least 3 points.
  • the reduction in TMS score is at least 4 points.
  • dystonia is improved.
  • gait is improved.
  • postural instability is improved.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen the subject's balance. In certain embodiments, the treatment improves balance.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0122]-[0152] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • a VMAT2 inhibitor for treating abnormal involuntary movement in a subject as set forth herein or in any of the embodiments above in paragraphs [0122]-[0152] above.
  • a VMAT2 inhibitor in the manufacture of a medicament for treating abnormal involuntary movement in a subject as set forth herein or in any of the embodiments above in paragraphs [0122]-[0152] above.
  • a composition comprising a VMAT2 inhibitor for use in treating abnormal involuntary movement in a subject, as set forth herein or in any of the embodiments above in paragraphs [0122]-[0152] above.
  • the VMAT2 inhibitor is a deuterium substituted tetrabenazine. In certain embodiments, the deuterium substituted tetrabenazine is deutetrabenazine. In certain embodiments, the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In certain embodiments, the plus isomeric form of tetrabenazine is an alpha isomer. In certain embodiments, the VMAT2 inhibitor is valbenazine.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved.
  • motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS).
  • TMS Total Motor Score
  • the reduction in TMS score is at least 2 points.
  • the reduction in TMS score is at least 3 points.
  • the reduction in TMS score is at least 4 points.
  • dystonia is improved.
  • gait is improved.
  • postural instability is improved.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen the subject's balance. In certain embodiments, the treatment improves balance.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0154]-[0173] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • a VMAT2 inhibitor for chorea and improving motor function in a subject with Huntington's disease as set forth herein or in any of the embodiments above in paragraphs [0154]-[0173] above.
  • a VMAT2 inhibitor in the manufacture of a medicament for chorea and improving motor function in a subject with Huntington's disease as set forth herein or in any of the embodiments above in paragraphs [0154]-[0173] above.
  • a composition comprising a VMAT2 inhibitor for use in chorea and improving motor function in a subject with Huntington's disease, as set forth herein or in any of the embodiments above in paragraphs [0154]-[0173] above.
  • VMAT2 inhibitor is a deuterium substituted tetrabenazine.
  • the subject has Huntington's disease. In certain embodiments, the subject has tardive dyskinesia. In certain embodiments, the subject has Tourette syndrome.
  • the deuterium substituted tetrabenazine is deutetrabenazine.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine.
  • the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the VMAT2 inhibitor is a plus isomeric form of tetrabenazine.
  • the plus isomeric form of tetrabenazine is an alpha isomer.
  • the VMAT2 inhibitor is valbenazine.
  • the daily amount of deutetrabenazine is administered in one dose or two doses.
  • the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg;
  • the first dose about 27 mg and the second dose is about 27 mg;
  • the first dose about 30 mg and the second dose is about 30 mg;
  • the first dose about 33 mg and the second dose is about 33 mg;
  • the first dose about 36 mg and the second dose is about 36 mg;
  • the first dose about 39 mg and the second dose is about 39 mg.
  • the first dose about 6 mg and the second dose is about 6 mg;
  • the first dose about 9 mg and the second dose is about 9 mg;
  • the first dose about 12 mg and the second dose is about 12 mg;
  • the first dose about 15 mg and the second dose is about 15 mg;
  • the first dose about 18 mg and the second dose is about 18 mg;
  • the first dose about 21 mg and the second dose is about 21 mg;
  • the first dose about 24 mg and the second dose is about 24 mg.
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.
  • the reduction in TMC score is at least 1 point. In certain embodiments, the reduction in TMC score is at least 1.5 points. In certain embodiments, the reduction in TMC score is at least 2.0 points. In certain embodiments, the reduction in TMC score is at least 2.5 points.
  • the improvement is over a pre-treatment, “baseline” TMC score of at least 8.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 10.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.0. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 12.7. In certain embodiments, the improvement is over a pre-treatment, “baseline” TMC score of at least 14.0.
  • chorea is reduced by at least 10%. In certain embodiments, chorea is reduced by at least 15%. In certain embodiments, chorea is reduced by at least 20%.
  • motor function is improved.
  • motor function is improved by a reduction of at least 1 point on the Total Motor Score (TMS).
  • TMS Total Motor Score
  • the reduction in TMS score is at least 2 points.
  • the reduction in TMS score is at least 3 points.
  • the reduction in TMS score is at least 4 points.
  • dystonia is improved.
  • gait is improved.
  • postural instability is alleviated.
  • treatment reduces the symptoms of parkinsonism.
  • the treatment does not worsen the subject's balance. In certain embodiments, the treatment improves balance.
  • the subject is much improved on the PGIC scale. In certain embodiments, the subject is very much improved on the PGIC scale. In certain embodiments, the subject is much improved on the CGIC scale. In certain embodiments, the subject is very much improved on the CGIC scale. In certain embodiments, the subject is much improved on the PGIC and CGIC scales. In certain embodiments, the subject is very much improved on the PGIC and CGIC scales.
  • the treatment improves physical functioning.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale from baseline.
  • the subject's physical functioning is improved as measured by the SF-36 physical functioning scale compared to untreated subjects.
  • the treatment improves swallowing.
  • treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, or fatigue.
  • treatment causes no significant parkinsonism or dysphagia.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0175]-[0196] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine, or a VMAT2 inhibitor for improving motor function in a subject with Huntington's disease, tardive dyskinesia, or Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0175]-[0196] above.
  • deutetrabenazine or a VMAT2 inhibitor
  • a composition comprising deutetrabenazine, or a VMAT2 inhibitor, for use in improving motor function in a subject with Huntington's disease, tardive dyskinesia, or Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0175]-[0196] above.
  • the tics are motor tics.
  • the tics are phonic tics.
  • the subject is between 6 and 16 years of age. In certain embodiments, the subject is between 12 and 18 years of age. In certain embodiments, the subject is between 6 and 18 years of age.
  • the daily amount of deutetrabenazine is about 6 mg to about 48 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. In certain embodiments, the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the daily amount of deutetrabenazine is administered with food.
  • the daily amount of deutetrabenazine is split into at least two doses.
  • the daily amount of deutetrabenazine is administered in two equal doses, consisting of a first dose and a second dose.
  • the motor or phonic tics are reduced ⁇ 25% as measured by the Total Tic Score of the Yale Global Tic Severity Scale.
  • the motor or phonic tics are reduced by 2 or more points on the Tourette Syndrome Clinical Global Impression (TS-CGI).
  • the motor or phonic tics are reduced by 1 or more points on the Tourette Syndrome Patient Global Impression of severity (TS-PGIS). In certain embodiments, the motor or phonic tics are reduced by 2 or more points on the Tourette Syndrome Patient Global Impression of severity (TS-PGIS).
  • the reduction is from baseline to at least two weeks.
  • the reduction is from baseline to at least four weeks. In certain embodiments, the reduction is from baseline to at least eight weeks. In certain embodiments, the reduction is from baseline to at least twelve weeks.
  • any embodiment above in paragraphs [0198]-[0211] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine, or a VMAT2 inhibitor for reducing motor or phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0198]-[0211] above.
  • deutetrabenazine, or a VMAT2 inhibitor in the manufacture of a medicament for reducing motor or phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0198]-[0211] above.
  • composition comprising deutetrabenazine, or a VMAT2 inhibitor, for use in reducing motor or phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0198]-[0211] above.
  • the daily amount of deutetrabenazine is about 6 mg to about 48 mg. In certain embodiments, the daily amount of deutetrabenazine is between 6 and 48 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. In certain embodiments, the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the daily amount of deutetrabenazine is administered with food.
  • the daily amount of deutetrabenazine is split into at least two doses.
  • the daily amount of deutetrabenazine is administered in two equal doses, consisting of a first dose and a second dose.
  • the subject is between 6 and 16 years of age. In certain embodiments, the subject is between 12 and 18 years of age. In certain embodiments, the subject is between 6 and 18 years of age.
  • the motor and phonic tics are reduced ⁇ 25% as measured by the Total Tic Score of the Yale Global Tic Severity Scale.
  • the motor or phonic tics are reduced by 2 or more points on the Tourette Syndrome Clinical Global Impression.
  • the reduction is from baseline to at least two weeks. In certain embodiments, the reduction is from baseline to at least four weeks. In certain embodiments, the reduction is from baseline to at least eight weeks. In certain embodiments, the reduction is from baseline to at least twelve weeks.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0213]-[0223] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine, or a VMAT2 inhibitor for reducing motor and phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0213]-[0223] above.
  • deutetrabenazine, or a VMAT2 inhibitor in the manufacture of a medicament for reducing motor and phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0213]-[0223] above.
  • composition comprising deutetrabenazine, or a VMAT2 inhibitor, for use in reducing motor and phonic tics in a subject with Tourette syndrome, as set forth herein or in any of the embodiments above in paragraphs [0213]-[0223] above.
  • a method of reducing tic severity as measured by the subject's Tourette Syndrome Patient Global Impression of Severity (TS-PGIS) in a subject with Tourette syndrome comprising the administration of about a daily amount of deutetrabenazine.
  • the method comprises: a) administering a daily amount of deutetrabenazine; and b) at least once every 4 weeks, assessing tic severity using the TS-PGIS.
  • the method additionally comprises: c) after assessing tic severity using the TS-PGIS, if the daily amount of deutetrabenazine is tolerable, increasing the daily amount of deutetrabenazine by at least 6 mg/day; d) repeating steps b) and c) until TS-PGIS is not further reduced or the daily amount of the deutetrabenazine is tolerated; and e) if any subsequent amount is not tolerated, decreasing the daily amount of deutetrabenazine downward by 6 mg/day.
  • the tics are motor tics.
  • the tics are phonic tics.
  • the subject is between 6 and 16 years of age. In certain embodiments, the subject is between 12 and 18 years of age. In certain embodiments, the subject is between 6 and 18 years of age.
  • the daily amount of deutetrabenazine is between 6 and 48 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg. In certain embodiments, the daily amount of deutetrabenazine is administered with food.
  • tic severity is assessed using the TS-PGIS at least every two weeks. In certain embodiments, tic severity is assessed using the TS-PGIS at least weekly. In certain embodiments, tic severity is assessed using the TS-PGIS at least monthly. In certain embodiments, tic severity is assessed using the TS-PGIS at least every three months.
  • the daily amount of deutetrabenazine is split into two doses.
  • the reduction is from baseline to at least two weeks. In certain embodiments, the reduction is from baseline to at least four weeks. In certain embodiments, the reduction is from baseline to at least eight weeks. In certain embodiments, the reduction is from baseline to at least twelve weeks.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0213]-[0234] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine for reducing tic severity as measured by the subject's Tourette Syndrome Patient Global Impression of Severity (TS-PGIS), as set forth herein or in any of the embodiments above in paragraphs [0213]-[0234] above.
  • composition comprising deutetrabenazine for use in reducing tic severity as measured by the subject's Tourette Syndrome Patient Global Impression of Severity (TS-PGIS), as set forth herein or in any of the embodiments above in paragraphs [0213]-[0234] above.
  • TS-PGIS Patient Global Impression of Severity
  • Also provided is a method of maintaining control of abnormal involuntary movements in a human subject with a movement disorder comprising administering to the subject a therapeutically effective daily amount of deutetrabenazine for a period of time sufficient to do one or more of the following: reduce chorea by at least 10%; improve motor function by at least 10%; improve physical functioning; improve swallowing; improve balance; reduce abnormal involuntary movements in subjects with tardive dyskinesia; reduce motor tics; reduce vocal/phonic tics; reduce motor and vocal/phonic tics; reduce impairment in subjects with Tourette syndrome; reduce the severity of Tourette syndrome; reduce the patient global impression of severity in subjects with Tourette Syndrome; and much or very much improve the subject's patient of clinical global impression of change.
  • the disorder is chosen from Huntington's disease, tardive dyskinesia, and Tourette syndrome.
  • reduction in chorea is measured by the Unified Huntington's Disease Rating Scale (UHDRS) or a subscale thereof; reduction in chorea is measured by the Total Maximal Chorea (TMC) score of the UHDRS; improvement in motor function is measured by the Total Motor Score (TMS) score of the UHDRS; improvement in physical functioning is measured by the SF-36 physical functioning scale; improvement in swallowing is measured by the Swallowing Disturbance Questionnaire (SDQ); improvement in balance is measured by the Berg Balance Test (BBT); reduction in abnormal involuntary movements in subjects with tardive dyskinesia is measured by the AIMS; reduction in motor tics in subjects with Tourette Syndrome is measured by the MTSS of the YGTSS; reduction in vocal/phonic tics in subjects with Tourette Syndrome is measured by the VTSS of the YGTSS; reduction in total (motor and vocal/phonic) tics is measured by the TTS of the YGTSS; reduction in impairment is measured
  • the daily amount of deutetrabenazine is about 6 mg to about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain embodiments, the daily amount of deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about 48 mg.
  • the daily amount of deutetrabenazine administered is less than or equal to about 48 mg, or less than or equal to about 36 mg for subjects concurrently receiving a strong CYP2D6 inhibitor.
  • the strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.
  • the strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and bupropion.
  • the sufficient period of time is at least four weeks. In certain embodiments, the sufficient period of time is at least eight weeks. In certain embodiments, the sufficient period of time is at least twelve weeks.
  • the reduction or improvement in the relevant measure or measures is by at least 10% over baseline. In certain embodiments, the reduction or improvement in the relevant measure or at least one of the measures is by at least 20% over baseline. In certain embodiments, the reduction or improvement in the relevant measure or at least one of the measures is by at least 30% over baseline. In certain embodiments, the reduction or improvement in the relevant measure or at least one of the measures is by at least 40% over baseline. In certain embodiments, the reduction or improvement in the relevant measure or at least one of the measures is by at least 50% over baseline.
  • the disorder is Huntington's disease.
  • the abnormal involuntary movement is chorea associated with Huntington's disease.
  • the disorder is tardive dyskinesia.
  • the disorder is Tourette syndrome.
  • the abnormal involuntary movement is a tic associated with Tourette syndrome.
  • the deutetrabenazine is a plus isomeric form of deutetrabenazine. In certain embodiments, the plus isomeric form of deutetrabenazine is an alpha isomer.
  • the treatment does not significantly prolong the QT interval. In certain embodiments, the treatment does not significantly change the QTcF value. In certain embodiments, the maximal increases in QTcF is less than 5 ms.
  • any embodiment above in paragraphs [0238]-[0246] above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
  • deutetrabenazine for maintaining control of abnormal involuntary movements in a human subject with a movement disorder as set forth herein or in any of the embodiments above in paragraphs [0238]-[0246] above.
  • deutetrabenazine in the manufacture of a medicament for maintaining control of abnormal involuntary movements in a human subject with a movement disorder as set forth herein or in any of the embodiments above in paragraphs [0238]-[0246] above.
  • composition comprising deutetrabenazine for maintaining control of abnormal involuntary movements in a human subject with a movement disorder, as set forth herein or in any of the embodiments above in paragraphs [0238]-[0246] above.
  • Tetrabenazine (Nitoman, Xenazine, Ro 1-9569), 1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is commonly prescribed for the treatment of Huntington's disease (Savani et al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), 7-17).
  • Tetrabenazine is subject to extensive oxidative metabolism, including O-demethylation of the methoxy groups, as well as hydroxylation of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655).
  • Adverse effects associated with the administration of tetrabenazine include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, depression, and Parkinsonism.
  • d 6 -Tetrabenazine (equivalently, deutetrabenazine, SD-809, or DTBZ) is a deuterated analog of tetrabenazine currently under clinical development.
  • the deutetrabenazine may be administered or formulated as part of a pharmaceutical composition wherein the composition has deuterium enrichment of at least 90% at each of the positions designated D. In certain embodiments, the composition has deuterium enrichment of at least 95% at each of the positions designated D. In certain embodiments, the composition has deuterium enrichment of at least 98% at each of the positions designated D.
  • d 6 -tetrabenazine is rapidly and extensively converted in the liver (similarly to non-isotopically enriched tetrabenazine) to major, active dihydrotetrabenazine (HTBZ) metabolites referred to as d 6 - ⁇ -HTBZ and d 6 - ⁇ -HTBZ (as a mixture of the + and ⁇ isomers) which have the structures below (+ isomers shown). These metabolites are believed to drive clinical efficacy.
  • HTBZ active dihydrotetrabenazine
  • Deuterium substituted tetrabenazines include, in addition to deutetrabenazine disclosed above, compounds as disclosed in U.S. Pat. No. 8,524,733, US 20100130480, and US 20120003330, and PCT/US2014/066740, filed Nov. 14, 2014. Examples of such compounds are given in the following structural formulas.
  • Formula I can include a single enantiomer, a mixture of the (+)-enantiomer and the ( ⁇ )-enantiomer, a mixture of about 90% or more by weight of the ( ⁇ )-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the ( ⁇ )-enantiomer, an individual diastereomer, or a mixture of diastereomers thereof.
  • the compounds of Formula II have alpha stereochemistry.
  • the compounds of Formula II have beta stereochemistry.
  • the compounds of Formula II are a mixture of alpha and beta stereoisomers.
  • the ratio of alpha/beta stereoisomers is at least 100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.
  • the ratio of beta/alpha stereoisomers is at least 100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.
  • R 50 -R 56 are deuterium, at least one of R 1 -R 49 is deuterium.
  • compounds have structural Formula III:
  • compounds have structural Formula IV:
  • Deuterium substituted tetrabenazine metabolites include, in addition to d 6 - ⁇ -HTBZ and d 6 - ⁇ -HTBZ disclosed above, compounds disclosed in of the following structural formulas.
  • alpha-dihydrotetrabenazine refers to either of the dihydrotetrabenazine stereoisomers having the structural formulas shown below, or a mixture thereof:
  • alpha or “alpha stereoisomer” or the symbol “ ⁇ ” as applied to a compound of Formula II refers to either of the stereoisomers of compounds of Formula II shown below, or a mixture thereof:
  • beta-dihydrotetrabenazine refers to either of the dihydrotetrabenazine stereoisomers having the structural formulas shown below, or a mixture thereof:
  • beta or “beta stereoisomer” or the symbol “ ⁇ ” as applied to a compound of Formula II refers to either of the stereoisomers of compounds of Formula II shown below, or a mixture thereof:
  • 3S,11bS enantiomer or the term “3R,11bR enantiomer” refers to either of the d 6 -tetrabenazine M4 metabolite stereoisomers having the structural formulas shown below:
  • a chemical structure may be drawn as either the 3S,11bS enantiomer or the 3R,11bR enantiomer, but the text of the specification may indicate that the 3S,11bS enantiomer, the 3R,11bR enantiomer, a racemic mixture thereof, or all of the foregoing may be intended to be described.
  • mixture of diastereomers refers to either of the d 6 -tetrabenazine M1 metabolite stereoisomers having the structural formulas shown below:
  • a chemical structure may be drawn as one of the diastereomers shown above, but the text of the specification may indicate that each individual diastereomer or a mixture thereof, or all of the foregoing may be intended to be described.
  • mixture of diastereomers refers to a mixture of the stereoisomers of compounds of Formula IV shown below:
  • Additional deuterium enriched tetrabenazine analogues include analogs of valbenazine.
  • Valbenazine (NBI-98854, CAS #1025504-59-9, (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate) is a VMAT2 inhibitor.
  • Valbenazine is currently under investigation for the treatment of movement disorders including tardive dyskinesia.
  • Valbenazine a valine ester of (+)- ⁇ -dihydrotetrabenazine, in humans is slowly hydrolyzed to (+)- ⁇ -dihydrotetrabenazine which is an active metabolite of tetrabenazine which is currently used for the treatment of Huntington's disease. Savani et al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), 7-17.
  • Dihydrotetrabenazine formed by hydrolysis of the valine ester of valbenazine, is subject to extensive oxidative metabolism, including O-demethylation of the methoxy groups, as well as hydroxylation of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655).
  • Adverse effects associated potentially associated with the administration of valbenazine include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, depression, and Parkinsonism.
  • Deuterium-substituted analogues of valbenazine include those as disclosed in WO2014120654. Examples of such compounds are given in the Formulas below.
  • R 1 -R 19 and R 21 -R 29 are independently selected from the group consisting of hydrogen and deuterium;
  • R 20 is selected from the group consisting of hydrogen, deuterium, —C(O)O-alkyl and —C(O)—C 1-6 alkyl, or a group cleavable under physiological conditions, wherein said alkyl or C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —NH—C(NH)NH 2 , —CO 2 H, —CO 2 alkyl, —SH, —C(O)NH 2 , —NH 2 , phenyl, —OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R 20 substituent is further optionally substituted with deuterium; and
  • At least one of R 1 -R 29 is deuterium or contains deuterium.
  • the compounds of Formula V have (+)-alpha stereochemistry.
  • the compounds of Formula V have ( ⁇ )-alpha stereochemistry.
  • the compounds of Formula V have (+)-beta stereochemistry.
  • the compounds of Formula V have ( ⁇ )-beta stereochemistry.
  • the compounds of Formula I are a mixture of alpha and beta stereoisomers.
  • the ratio of alpha/beta stereoisomers is at least 100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.
  • the ratio of beta/alpha stereoisomers is at least 100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.
  • R 1 -R 19 and R 21 -R 39 are independently selected from the group consisting of hydrogen and deuterium;
  • At least one of R 1 -R 19 and R 21 -R 39 is deuterium.
  • R 20 is selected from the group consisting of —C(O)O-alkyl and —C(O)—C 1-6 alkyl, or a group cleavable under physiological conditions, wherein said alkyl or C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —NH—C(NH)NH 2 , —CO 2 H, —CO 2 alkyl, —SH, —C(O)NH 2 , —NH 2 , phenyl, —OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any R 20 substituent is further optionally substituted with deuterium.
  • the compounds as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen.
  • Deuterium (D) is a naturally occurring, non-radioactive, stable isotope of hydrogen (H), that contains both a proton and a neutron in its nucleus.
  • H isotope of hydrogen
  • the presence of the neutron doubles the mass of D when compared to H, which in turn increases the vibrational frequency of the C-D covalent bond as compared to the C—H covalent bond.
  • An increase in the vibrational frequency of a covalent bond results in an increase in the activation energy required to break that bond, and consequentially an increase in the bond strength.
  • This increased covalent bond strength can in certain instances alter the kinetics of the covalent bond cleavage resulting in what is known as the Kinetic Isotope Effect (KIE).
  • KIE Kinetic Isotope Effect
  • the replacement of a covalent C—H bond with a covalent C-D bond can result in a meaningful deuterium KIE.
  • a large deuterium KIE for a drug that is a CYP450 substrate can in certain instances lead to an improvement in the pharmacokinetic parameters of that drug, which can potentially result in a differentiation between the deuterated and the non-deuterated drugs.
  • the covalent C-D bonds in deutetrabenazine satisfy a number of chemical and biological criteria which work in concert to provide a deuterium KIE that is large enough to slow down the O-demethylation of the active metabolites of deutetrabenazine as compared to tetrabenazine. It is important to note that the magnitude of this deuterium KIE could not have been predicted a priori, and hence it was not possible to know ahead of time if the replacement of a C—H covalent bond in tetrabenazine with a C-D covalent bond would have led to a noticeable and/or improved biological difference.
  • Deutetrabenazine or d 6 -Tetrabenazine is a VMAT2 Inhibitor.
  • the covalent nature of the C-D bond can be established by spectroscopic methods such as Infrared (IR) Spectroscopy.
  • IR Infrared
  • the characteristic IR absorption of C-D stretches at approximately 2000-2300 cm-1 is often used by researchers as site-specific and non-perturbative probes for protein studies (Miller and Corcelli, 2009; Zimmermann et al., 2011).
  • d 6 -tetrabenazine has distinct IR absorptions at 2060-2250 cm-1 which are attributed to the C-D stretches. These absorption bands are absent from the IR spectrum of the non-deuterated form of tetrabenazine.
  • d 6 -tetrabenazine is not a salt form of tetrabenazine.
  • the mass spectrum of deutetrabenazine displays the protonated molecular ion at m/z 324.18 [M+1]. This agrees with the predicted mass number of d 6 -tetrabenazine as an intact molecule.
  • deuterium atoms in d 6 -tetrabenazine do not exchange with hydrogen under normal physiological conditions.
  • the pKa of non-conjugated aliphatic C—H bonds is in the range of 45-50, which means that at equilibrium, the ratio of dissociated to non-dissociated species is less than 10-45.
  • the C—H bonds of the methoxy groups of tetrabenazine, and by extension, the C-D bonds of the methoxy groups of d 6 -tetrabenazine are even less acidic, with a pKa value approaching 50. This means that one would need to increase the pH of an aqueous solution to more than 45 before any of the deuterium atoms in deutetrabenazine can potentially start exchanging with hydrogen atoms.
  • d 6 -tetrabenazine or deutetrabenazine has been administered to humans in clinical studies, and subject to various in vitro incubations with multiple enzymatic processes.
  • the known active metabolites as well as further downstream metabolites have been monitored in vitro incubates and/or in human plasma by LC/MS/MS methods.
  • These metabolites have been synthesized and confirmed to contain the expected trideuteromethyl groups (—CD 3 ), confirming that the covalent C-D bonds in deutetrabenazine are stable and carried into the downstream metabolites of deutetrabenazine.
  • Deutetrabenazine has a differentiated pharmacokinetics profile compared to d 0 -tetrabenazine.
  • KIE deuterium kinetic isotope effect
  • a medicine with a longer half-life may result in greater efficacy, better safety and tolerability, improved quality of life and potential for cost savings in the long term.
  • Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not.
  • the deuteration approach has demonstrated the ability to slow the metabolism of tetrabenazine and attenuate interpatient variability.
  • any one of the listed items can be employed by itself or in combination with any one or more of the listed items.
  • the expression “A and/or B” is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination.
  • the expression “A, B and/or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.
  • abnormal refers to an activity or feature that differs from a normal activity or feature.
  • abnormal muscular activity refers to muscular activity that differs from the muscular activity in a healthy subject.
  • the abnormal activity may be decreased or increased in comparison to normal activity.
  • An increase in muscular activity can result in excessive abnormal movements, excessive normal movements, or a combination of both.
  • AE adverse event
  • An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or laboratory parameter that develops or worsens in severity during the course of this study, or significant worsening of the disease under study or of any concurrent disease, whether or not considered related to the study drug.
  • a new condition or the worsening of a pre-existing condition will be considered an adverse event.
  • Stable chronic conditions (such as arthritis) that are present before study entry and do not worsen during this study will not be considered adverse events.
  • a mild AE is one which does not limit the subject's activities; a moderate AE is one which causes some limitation of usual activities; and a severe AE is one which renders a subject unable to carry out usual activities.
  • a “treatment-related adverse event” is an adverse event which, in a physician's or clinician's judgment, is related to the drug administered. Such a determination should be understood to often not reduce to a yes/no question, but may lie on a continuum wherein it is more or less likely that the AE is treatment-related, including the closeness of manifestation of the event to dosing, the disappearance of the AE upon discontinuation or reduction in dose of the drug, and the failure of other factors (e.g., preexisting conditions, environmental factors, etc.) to explain the AE.
  • CYP2D6 inhibitor refers to a drug which is inhibits CYP2D6, therefore making it unavailable to metabolize other substrate compounds; co-administration of a drug metabolized by CYP2D6 with a CYP2D6 inhibitor should be carried out with caution and often at a reduced dosage, as the plasma concentration of the drug will often be.
  • CYP2D6 inhibitors include amiodarone, celecoxib, chloroquine, chlorpromazine, cimetidine, citalopram, clomipramine, codeine, deiavirdine, desipramine, dextroprpoxyphene, diltiazem, doxorubicin, entacapone (high dose), fluoxetine, fluphenazine, fluvaxamine, haloperidol, labetalol, lobeline, lomustine, methadone, mibefradil, moclobemide, nortuloxeline, paroxetine, perphenazine, propafenone, quinacrine, quinidine, ranitidine, risperidone, ritonavir, serindole, sertraline, thioridazine, valproic acid, venlafaxine, vinblastine, vincristine, vinorelbine, and yohimbine. Strong CYP2
  • degree as used herein in reference to control of abnormal muscular activity or abnormal involuntary movement (e.g., chorea) is meant to be synonymous with “level”.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disease”, “syndrome”, and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
  • treat is meant to include alleviating or abrogating a disorder or one or more of the symptoms associated with a disorder; or alleviating or eradicating the cause(s) of the disorder itself.
  • treatment of a disorder is intended to include prevention.
  • prevent refers to a method of delaying or precluding the onset of a disorder; and/or its attendant symptoms, barring a subject from acquiring a disorder or reducing a subject's risk of acquiring a disorder.
  • tolerable and “tolerability” refer to that amount of deuterium-substituted tetrabenazine (e.g., deutetrabenazine) or other drug (e.g., deuterium-substituted VMAT inhibitor, or valbenazine) which produces low rates of adverse events such as somnolence, irritability, fatigue, vomiting and nausea in patients and where the adverse events do not lead to dose reduction of the deuterium substituted tetrabenazine or other drug, suspension of the deuterium substituted tetrabenazine or other drug, or withdrawal of the drug deuterium substituted tetrabenazine or other drug.
  • deuterium-substituted tetrabenazine e.g., deutetrabenazine
  • other drug e.g., deuterium-substituted VMAT inhibitor, or valbenazine
  • the deuterium substituted tetrabenazine is also considered tolerable if any underlying symptoms such as depression, anxiety, suicidality, parkinsonism in patients having diseases or conditions, such as Huntington's disease, tardive dyskinesia or Tourette syndrome, are not worsened.
  • Tolerable and tolerability shall also refer to that amount of deutetrabenazine (or other drug, if applicable) which does not necessitate a downward adjustment in regular (e.g., daily) dose, or a suspension of dose, for example due to adverse effects.
  • a tolerable amount may vary from between subjects, and also within a subject over the course of a disease or course of treatment.
  • the term “adequate” as used herein in reference to control of abnormal muscular activity or abnormal involuntary movement (e.g., chorea) in a subject refers a level of control which is observable and satisfactory to the subject.
  • the clinician, investigator, in consultation with the subject will determine when an adequate level of control of abnormal muscular activity or abnormal involuntary movement (e.g., chorea) has been achieved.
  • the adequacy of a level of control of abnormal muscular activity or abnormal involuntary movement provided by an amount of a drug will be affected by the tolerability of that amount, and will often be the maximum tolerated amount which yields an observable increase in control (the “optimal” amount).
  • the amount of deutetrabenazine may be increased on a weekly basis until there is adequate control of chorea, the subject experiences a protocol defined “clinically significant” adverse event (defined as related to study medication and either a) moderate or severe in intensity or b) meets the criteria for a Serious Adverse Event (SAE), or the maximal allowable dose is reached.
  • SAE Serious Adverse Event
  • An adequate level may vary from between subjects, and also within a subject over the course of a disease or course of treatment.
  • abnormal involuntary movement includes involuntary movements associated with or caused by movement disorders.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like.
  • a primate e.g., human, monkey, chimpanzee, gorilla, and the like
  • rodents e.g., rats, mice, gerbils, hamsters, ferrets, and the like
  • lagomorphs e.g., pig, miniature pig
  • swine e.g., pig, miniature pig
  • equine canine
  • feline feline
  • the GTS-QOL consists of two parts.
  • the first part is typically a twenty-seven question assessment of various aspects of how tics affect the subject's life, each to be rated on a five-choice scale of no problem, slight problem, moderate problem, marked problem, or severe problem. Subscales combining some of these aspects can be focused upon, such as, e.g., the physical/activities of daily living (ADL) subscale.
  • the second part is a simple rating of the subject's life satisfaction, where 100 is extremely satisfied and 0 is extremely dissatisfied.
  • the SF-36 Physical Functioning Score.
  • the SF-36 is a short-form health survey with 36 questions used to evaluate health-related quality of life (Ware, 1996).
  • the SF-36 has been useful in comparing specific populations and comparing the relative burden of various diseases.
  • the SF-36 has been evaluated in HD patients and shown to have robust construct validity and test-retest reliability and was also able to discriminate from age-matched controls and normative data on the 10-item physical functioning scale (Ho, 2004). While the entire SF-36 was administered in this study, the physical functioning scale (also known as the PF-10) was analyzed as a key secondary endpoint.
  • the physical functioning scale is a 10-item subset of the SF-36 which examines a subject's perceived health-related limitations with physical activities.
  • the SF-36 physical functioning score is a 10-item scale where subjects rate their ability to perform routine physical activities such as walking, climbing stairs, bathing, or dressing. Given the potential for chorea to interfere with basic motor skills, gait, and walking it is not unexpected that subjects with more impaired function would experience greater benefit on this measure.
  • the Tourette Syndrome Patient Global Impression of Severity is a novel five-point scale in which 1 indicates no tics, 2 indicates mild tics (not distressing, noticeable, or interfering with daily life), 3 indicates moderate (can be distressing, noticeable, and sometimes interfering with daily life), 4 indicates marked (very distressing, noticeable, and interfering with daily life), and 5 indicates severe (severely distressing, always noticeable, and preventing of most daily activities).
  • the Tic-Free Interval is a five-point scale in which 1 indicates an interval of at least one day since the last tic, 2 indicates an interval of between 6 hours to less than one day since the last tic, 3 indicates an interval of between one hour and less than 6 hours since the last tic, 4 indicates an interval of between five minutes to less than one hour since the last tic, and 5 indicates less than five minutes since the last tic.
  • the TS-CGI is a seven-point scale scored by the clinician, in which 1 indicates normal or no tics, 2 indicates tics may or may not be present, 3 indicates mild, observable motor and/or phonic tics that may or may not be noticed, would not call attention to the individual, and are associated with no distress or impairment, 4 indicates moderate, observable motor and/or phonic tics that would always be noticed, would call attention to the individual, and may be associated with some distress or impairment, 5 indicates marked, exaggerated motor and/or phonic tics that are disruptive, would always call attention to the individual, and are always associated with significant distress or impairment, 6 indicates severe, extremely exaggerated motor and/or phonic tics that are disruptive, would always call attention to the individual, and are associated with injury or inability to carry out daily functions, and 7 indicates extreme, incapacitating tics.
  • the YGTSS is a comprehensive evaluation of various aspects and severity of motor and phonic tics.
  • TTS total tic severity
  • impairment of the patient's life is scored on a scale of 0 to 50, wherein 0 indicates no impairment, 10 is minimal, 20 is mild, 30 is moderate, 40 is marked, and 50 is severe, yielding an impairment score.
  • GSS Global Severity Score
  • the Tourette Syndrome Patient Global Impression of Change (TS-PGIC) is a seven-point scale in which ⁇ 3 indicates very much worse, ⁇ 2 indicates much worse, ⁇ 1 indicated minimally worse, 0 indicated no change, 1 indicates minimally improved, 2 indicates much improved, and 3 indicates very much improved.
  • the GTS-QOL consists of two parts.
  • the first part is typically a twenty-seven question assessment of various aspects of how tics affect the subject's life, each to be rated on a five-choice scale of no problem, slight problem, moderate problem, marked problem, or severe problem.
  • the second part is a simple rating of the subject's life satisfaction, where 100 is extremely satisfied and 0 is extremely dissatisfied.
  • the Tic-Free Interval is a five-point scale in which 1 indicates an interval of at least one day since the last tic, 2 indicates an interval of between 6 hours to less than one day since the last tic, 3 indicates an interval of between one hour and less than 6 hours since the last tic, 4 indicates an interval of between five minutes to less than one hour since the last tic, and 5 indicates less than five minutes since the last tic.
  • VMAT2 refers to vesicular monoamine transporter 2, an integral membrane protein that acts to transport monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.
  • VMAT2-mediated disorder refers to a disorder that is characterized by abnormal VMAT2 activity.
  • a VMAT2-mediated disorder may be completely or partially mediated by modulating VMAT2.
  • a VMAT2-mediated disorder is one in which inhibition of VMAT2 results in some effect on the underlying disorder e.g., administration of a VMAT2 inhibitor results in some improvement in at least some of the patients being treated.
  • VMAT2 inhibitor refers to the ability of a compound disclosed herein to alter the function of VMAT2.
  • a VMAT2 inhibitor may block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event.
  • VMAT2 inhibitor also refers to altering the function of VMAT2 by decreasing the probability that a complex forms between a VMAT2 and a natural substrate
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base.
  • Therapeutically acceptable salts include acid and basic addition salts.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.
  • compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • compounds may be delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds disclosed herein may be formulated or administered using any of formulations and methods disclosed in U.S. patent application Ser. No. 14/030,322, filed Sep. 18, 2013, which is hereby incorporated by reference in its entirety.
  • the compounds can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the disorder being treated. Also, the route of administration may vary depending on the disorder and its severity.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.
  • the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disorder is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • VMAT2-mediated disorder comprising administering to a subject having or suspected of having such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • VMAT2-mediated disorders include, but are not limited to, chronic hyperkinetic movement disorders, Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and/or any disorder which can lessened, alleviated, or prevented by administering a VMAT2 inhibitor.
  • Movement disorders include akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesias (e.g., paroxysmal), dystonia (general, segmental, focal) including blepharospasm, writer's cramp (limb dystonia), laryngeal dystonia (spasmodic dysphonia), and oromandibular dystonia, essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's Disease, multiple system atrophy (Shy Drager Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease levodopa-induced dyskinesia, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis (cervical dystonia), spasticity due to stroke, cerebral palsy, multiple
  • a method of treating abnormal muscular activity, abnormal involuntary movement, or movement disorder comprises administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to affect: (1) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit; (3) decreased inhibition of, and/or metabolism by at least one cytochrome P 450 or monoamine oxidase isoform in the subject; (4) decreased metabolism via at least one polymorphically-expressed cytochrome P 450 isoform in the subject; (5) at least one statistically-significantly improved disorder-control and/or disorder-eradication endpoint; (6) an improved clinical effect during the treatment of the disorder, (7) prevention of recurrence, or delay of decline or appearance, of abnormal alimentary or hepatic parameters as the primary clinical benefit, or (8) reduction
  • inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof is decreased; average plasma levels of the compound as disclosed herein are increased; average plasma levels of a metabolite of the compound as disclosed herein are decreased; inhibition of a cytochrome P 450 or monoamine oxidase isoform by a compound as disclosed herein is decreased; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P 450 isoform is decreased; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or by greater than about 50% as compared to the corresponding non-isotopically enriched compound.
  • Plasma levels of the compound as disclosed herein, or metabolites thereof may be measured using the methods described by Li et al. Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950; Jindal, et al., Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7; Schwartz, et al., Biochemical Pharmacology 1966, 15(5), 645-55; Mehvar, et al., Drug Metabolism and Disposition 1987, 15(2), 250-5; Roberts et al., Journal of Chromatography, Biomedical Applications 1981, 226(1), 175-82; and any references cited therein or any modifications made thereof.
  • cytochrome P 450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11
  • Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAO A , and MAO B .
  • the inhibition of the cytochrome P 450 isoform is measured by the method of Ko et al. ( British Journal of Clinical Pharmacology, 2000, 49, 343-351).
  • the inhibition of the MAO A isoform is measured by the method of Weyler et al. ( J. Biol Chem. 1985, 260, 13199-13207).
  • the inhibition of the MAO B isoform is measured by the method of Uebelhack et al. ( Pharmacopsychiatry, 1998, 31, 187-192).
  • Examples of polymorphically-expressed cytochrome P 450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
  • liver microsomes The metabolic activities of liver microsomes, cytochrome P 450 isoforms, and monoamine oxidase isoforms are measured by the methods described herein.
  • improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to:
  • diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “ ⁇ -GTP,” or “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in “Diagnostic and Laboratory Test Reference”, 4 th edition, Mosby, 1999. These assays are run by accredited laboratories according to standard protocol.
  • certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the compounds disclosed herein may also be combined or used in combination with other agents useful in the treatment of VMAT2-mediated disorders.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein.
  • a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.
  • the compounds disclosed herein can be combined with one or more dopamine precursors, including, but not limited to, levodopa.
  • the compounds disclosed herein can be combined with one or more DOPA decarboxylase inhibitors, including, but not limited to, carbidopa.
  • the compounds disclosed herein can be combined with one or more catechol-O-methyl transferase (COMT) inhibitors, including, but not limited to, entacapone and tolcapone.
  • CCT catechol-O-methyl transferase
  • the compounds disclosed herein can be combined with one or more dopamine receptor agonists, including, but not limited to, apomorphine, bromocriptine, ropinirole, and pramipexole.
  • dopamine receptor agonists including, but not limited to, apomorphine, bromocriptine, ropinirole, and pramipexole.
  • the compounds disclosed herein can be combined with one or more neuroprotective agents, including, but not limited to, selegiline and riluzole.
  • the compounds disclosed herein can be combined with one or more NMDA antagonists, including, but not limited to, amantadine.
  • the compounds disclosed herein can be combined with one or more anti-psychotics, including, but not limited to, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, periciazine, thioridazine, mesoridazine, pipotiazine, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone, sertindole, ziprasidone, flupentixol, clopenthixol
  • the compounds disclosed herein can be combined with one or more benzodiazepines (“minor tranquilizers”), including, but not limited to alprazolam, adinazolam, bromazepam, camazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate, estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, and chlordiazepoxide.
  • minor tranquilizers including, but not limited to alprazolam, adinazolam, bromaze
  • the compounds disclosed herein can be combined with olanzapine or pimozide.
  • the compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, anti-retroviral agents; CYP3A inhibitors; CYP3A inducers; protease inhibitors; adrenergic agonists; anti-cholinergics; mast cell stabilizers; xanthines; leukotriene antagonists; glucocorticoids treatments; local or general anesthetics; non-steroidal anti-inflammatory agents (NSAIDs), such as naproxen; antibacterial agents, such as amoxicillin; cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib; anti-fungal agents, such as isoconazole; sepsis treatments, such as drotrecogin- ⁇ ; steroidals, such as hydrocortisone; local or general anesthetics, such as ketamine; norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine
  • squalene synthetase inhibitors include fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochiorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethiazide, polythiazide, benzothlazide, ethacrynic acid, tric
  • metformin glucosidase inhibitors
  • glucosidase inhibitors e.g., acarbose
  • insulins meglitinides (e.g., repaglinide)
  • meglitinides e.g., repaglinide
  • sulfonylureas e.g., glimepiride, glyburide, and glipizide
  • thiozolidinediones e.g.
  • certain embodiments provide methods for treating VMAT2-mediated disorders in a subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of VMAT2-mediated disorders.
  • the compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in US 20100130480 (paragraphs [0093]-[0121]), US 20120003330 (paragraphs [0104]-[0162]), WO 2005077946; WO 2008/058261; EP 1716145; Lee et al., J. Med. Chem., 1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldt et al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org.
  • Isotopic hydrogen can be introduced into a compound as disclosed herein by synthetic techniques that employ deuterated reagents, whereby incorporation rates are pre-determined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions.
  • Synthetic techniques where tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry required.
  • Exchange techniques on the other hand, may yield lower tritium or deuterium incorporation, often with the isotope being distributed over many sites on the molecule.
  • specific examples of compounds of the present invention include a compound selected from the list described in paragraph [0122] of US 20100130480 and paragraph [0163] of US 20120003330, which are hereby incorporated by reference.
  • Compounds may be formulated for use in the dosage regimens and methods disclosed herein by methods known in the art, e.g., as disclosed in US2014/0336386. Examples of these formulations are provided below.
  • Table 1 below discloses the elements of a 350 mg total weight gastro-erosional granulation formulation tablet comprising 15 mg (RR, SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.
  • d 6 -Tetrabenazine (milled) is combined along with Mannitol Powder, Microcrystalline Cellulose, PVP K29/32 and Tween 80 (Polysorbate 80) into a high shear granulator and initially dry mixed at high impeller and chopper speed for 5 minutes. While mixing at high impeller speed and low chopper speed, Purified Water is added to the mixing powders to granulate the material. Additional mixing and water addition with high impeller and high chopper speed continues until the desired granulation end-point is achieved. The resulting granulation is wet screened to break up any oversized agglomerates and the material is added to a fluid bed drier and dried at 60° C. until the desired L.O.D.
  • the dried material is sieved through a #20 mesh screen and the oversized material is milled to a particle size of just under 20 mesh in size.
  • the dried and sized material is combined with Spray Dried Mannitol and POLYOX® N60K into a diffusive mixer (V-Blender) where it is blended for 15 minutes.
  • Magnesium Stearate is then passed through a #30 mesh screen and added to the blended material in the V-Blender.
  • the contents are then lubricated for 3 minutes and discharged for tablet compression. Using a rotary tablet press fitted with punches and dies of the desired shape and size, the lubricated blend is compressed into tablets of a theoretical weight of 350 mg.
  • Table 2 discloses the elements of a 350 mg total weight gastro-erosional granulation formulation tablet comprising 7.5 mg d 6 -tetrabenazine. Same process as described for Example 1.
  • Table 3 below discloses the elements of a 700 mg total weight gastro-retentive formulation tablet comprising 15 mg d 6 -tetrabenazine.
  • the gastro-retentive tablet is an elongated capsule having dimensions of approximately 0.7087 in. long by 0.3071 in. wide, having rounded ends with a cup depth of 0.0540 in. on each opposing side.
  • Table 4 below discloses the elements of a 700 mg total weight gastro-retentive formulation tablet comprising 7.5 mg d 6 -tetrabenazine.
  • the gastro-retentive tablet is an elongated capsule having dimensions of approximately 0.7087 in. long by 0.3071 in. wide, having rounded ends with a cup depth of 0.0540 in. on each opposing side. Same process as described for Example 1. But theoretical compression weight is 700 mg.
  • Table 5 below discloses the elements of a 125 mg total weight immediate-release tablet comprising 6 mg d 6 -tetrabenazine.
  • d 6 -Tetrabenazine (milled) is combined along with Mannitol Powder, Microcrystalline Cellulose, Sodium Starch Glycolate, PVP K29/32 and Tween 80 (Polysorbate 80) into a high shear granulator and initially dry mixed at high impeller and chopper speed for 5 minutes. While mixing at high impeller speed and low chopper speed, Purified Water is added to the mixing powders to granulate the material. Additional mixing and water addition with high impeller and high chopper speed continues until the desired granulation end-point is achieved. The resulting granulation is wet screened to break up any oversized agglomerates and the material is added to a fluid bed drier and dried at 60° C.
  • the dried material is sieved through a #20 mesh screen and the oversized material is milled to a particle size of just under 20 mesh in size.
  • the dried and sized material is combined with Spray Dried Mannitol and Sodium Starch Glycolate.
  • the deutetrabenazine may be administered or formulated as part of a pharmaceutical composition as disclosed in tables 1-5 above.
  • First-HD was a randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and tolerability of deutetrabenazine in subjects with chorea associated with HD. This trial was conducted in the United States and Canada, in collaboration with the Huntington Study Group.
  • Subjects in First-HD were treated with deutetrabenazine or placebo, starting at 6 mg once per day and titrating weekly to doses of up to 24 mg twice per day (48 mg total maximum daily dose).
  • a total of 90 subjects (45 in each group) were enrolled for evaluation over 13 weeks.
  • Subjects were individually titrated to an optimal dose over up to eight weeks, received maintenance therapy at the optimal dose for four weeks, and were taken off study medication in the final week of the trial.
  • the study population was typical for subjects with chorea associated with HD.
  • the mean age of the subjects was 53.7 years.
  • the majority of subjects were white (92.2%) and male (55.6%).
  • the mean CAG repeat length among the subject population was 43.9.
  • the mean TMC score was 12.7 in the overall population (range 8.0-19.5).
  • the primary efficacy endpoint for the study was the change from baseline to maintenance therapy (average of Week 9 and Week 12 values) in the maximal chorea score of the UHDRS.
  • the total maximal score, or TMC is a clinician-based, quantitative assessment of chorea in seven body regions: face, mouth/tongue, trunk, and the four extremities, with higher scores representing more severe chorea. This is the same endpoint that was accepted by the FDA when it considered and approved tetrabenazine in 2008 (NDA 21894).
  • the total motor score (TMS) of the UHDRS was prespecified as an additional efficacy endpoint in First-HD.
  • the TMS assesses all the motor features of HD, including items addressing characteristic motor abnormalities other than chorea, such as dystonia, gait, parkinsonism, and postural instability.
  • the PGIC and CGIC are single-item questionnaires that ask the subject and investigator, respectively, to assess a subject's overall HD symptoms at specific visits after initiating therapy. Both assessments use a 7-point Likert Scale, with responses ranging from Very Much Worse ( ⁇ 3) to Very Much Improved (+3) to assess overall response to therapy. Patients and clinicians were asked, “With respect to your (or the subject's) overall Huntington's disease symptoms, how would you describe yourself (or the subject) compared to immediately before starting study medication.” Treatment success according to these scales was defined as a rating of Much Improved or Very Much Improved at Week 12. Subjects who did not have a response at Week 12 were assumed to be treatment failures.
  • AE Adverse events
  • Categories of AEs of particular focus included those known to be associated with tetrabenazine use:
  • HADS Hospital Anxiety and Depression Scale
  • C-SSRS Columbia Suicide Severity Rating Scale
  • SDQ Swallowing Disturbance Questionnaire
  • UPD Unified Parkinson's Disease Rating Scale
  • BARS Barnes Akathisia Rating Scale
  • ESS Epworth Sleepiness Scale
  • the Swallowing Disturbance Questionnaire was used prospectively to assess swallowing impairment during the study, as dysphagia is a common problem in patients with HD.
  • This 15-item assessment has been validated in patients with Parkinson's disease and has been shown to be a sensitive and accurate tool for identifying patients with swallowing disturbances arising from different etiologies.
  • the SDQ is recommended by the National Institute of Neurological Disorders and Stroke Common data elements for assessing swallowing impairment in Parkinson's disease, and thus is also relevant for patients with HD, given they may have bradykinesia and other parkinsonian symptoms as part of their illness.
  • the mean dose at the end of treatment period was 39.7 mg (SD 9.3 mg, range 12-48 mg) in the deutetrabenazine group and 43.3 mg (7.6 mg, range 12-48 mg) in the placebo group.
  • Mean dosage for the 10 deutetrabenazine group subjects with impaired CYP2D6 function was 34.8 mg (3.8 mg, range 30-42 mg).
  • the overall compliance rates were 94.1% and 95.1% for placebo and deutetrabenazine groups, respectively.
  • TMC Total Maximal Chorea Score
  • TMC score at a given time point is determined from Item 12 of the UHDRS. Change in TMC is the difference between baseline and maintenance therapy values. The baseline value is the mean of the Screening and Day 0 values and the maintenance therapy value is the mean of the Week 9 and Week 12 values.
  • subjects receiving deutetrabenazine achieved a significant reduction of 2.5 units on the TMC score from baseline to maintenance therapy compared with placebo (p ⁇ 0.0001). This reduction in maximal chorea represented a reduction of 21 percentage points compared with placebo (p ⁇ 0.0001).
  • Deutetrabenazine (DTBZ) was administered at approximately half the daily dose of tetrabenazine. The efficacy of deutetrabenazine was therefore achieved at about half the daily dose of tetrabenazine.
  • TMS Total Motor Score
  • deutetrabenazine may represent a superior choice for treatment of movement disorders generally. It is noteworthy that deutetrabenazine achieved efficacy at about half the daily dose of tetrabenazine.
  • PGIC Patient Global Impression of Change
  • CGIC Clinical Global Impression of Change
  • Improvement in these physician and patient assessment scores indicate that the improvement measured by the TMC and TMS translated into improvement of HD symptoms and further supports the clinical benefit of deutetrabenazine.
  • the Physical Functioning Score of the SF-36 was selected as a key secondary endpoint because it is a patient-reported instrument that has been used in many disease states and it assesses physical activities relevant to patients living with HD.
  • the 10-item physical functioning score queries patients regarding self-care such as bathing, dressing, lifting or carrying groceries, climbing one or more flights of stairs, bending, kneeling, walking 100 yards or more, and moderate to vigorous activities.
  • the SF-36 physical functioning score has been shown to measure impairment experienced by people living with HD.
  • the BBT is a 14-item assessment of balance that was used to evaluate if reducing chorea had an impact on balance, since many medications currently used to treat chorea may worsen balance.
  • Deutetrabenazine was generally well tolerated.
  • the overall rates of adverse events (AEs) were the same between the deutetrabenazine and placebo groups, with (60.0%) of subjects in each group experiencing at least one AE. There were no deaths in the study.
  • AEs chronic obstructive pulmonary disease
  • HADS Hospital Anxiety and Depression Scale
  • C-SSRS Columbia Suicide Severity Rating Scale
  • SDQ Swallowing Disturbance Questionnaire
  • UPD Unified Parkinson's Disease Rating Scale
  • BARS Barnes Akathisia Rating Scale
  • ESS Epworth Sleepiness Scale
  • the Swallowing Disturbance Questionnaire was used prospectively to assess swallowing impairment during the study, as dysphagia is a common problem in patients with HD.
  • This 15-item assessment has been validated in patients with Parkinson's disease and has been shown to be a sensitive and accurate tool for identifying patients with swallowing disturbances arising from different etiologies.
  • the SDQ is recommended by the National Institute of Neurological Disorders and Stroke Common data elements for assessing swallowing impairment in Parkinson's disease, and thus is also relevant for patients with HD, given they may have bradykinesia and other parkinsonian symptoms as part of their illness.
  • FIG. 2 presents the mean change from baseline in the SDQ by over time, demonstrating a significant improvement in swallowing with deutetrabenazine treatment, compared with placebo.
  • the UHDRS rating scale was assessed throughout the First-HD Study to monitor for safety. Evaluation of the parkinsonism subscore of the UHDRS Motor Assessment (Part I) did not identify evidence of parkinsonism in subjects treated with deutetrabenazine or placebo, consistent with the absence of extrapyramidal symptom AEs. These results were further supported by the lack of meaningful changes in either treatment group on the UPDRS dysarthria question.
  • the UHDRS Behavioral Assessment demonstrated improvement in the in the mean total behavior score for deutetrabenazine-treated subjects compared with the placebo group, however the difference did not achieve statistical significance. Importantly, there was no worsening of depressed mood, apathy, self-esteem, irritability, aggressive behavior, suicidal thoughts, hallucinations, or delusions. The improvement in the overall score was driven by differences in anxiety and compulsive behavior ( FIG. 4 A-C).
  • variable pharmacokinetics of tetrabenazine can affect its tolerability and limit its clinical use.
  • the half-lives of the circulating active metabolites, ⁇ - and ⁇ -dihydrotetrabenazine, are short. These short half-lives necessitate frequent dosing and result in large fluctuations in plasma concentrations.
  • the high peak concentrations and variability in plasma levels associated with tetrabenazine may contribute to the poor tolerability that is often observed.
  • the prescribing information for tetrabenazine contains several warnings regarding adverse effects and the potential for safety issues:
  • the study thus comprised two cohorts.
  • the Rollover Cohort (75 subjects) successfully completed the First-HD study described above, including a 1-week washout; the Switch Cohort (37 subjects) switched overnight from stable dosing ( ⁇ 8 weeks) with tetrabenazine to deutetrabenazine based on a conversion method designed to achieve comparable systemic exposure to total ⁇ and ⁇ metabolites.
  • HADS depression subscale of the Hospital Anxiety and Depression Scale
  • SDQ Disturbance Questionnaire
  • UPDS Unified Parkinson's Disease Rating Scale
  • the conversion method applied was based on modeling and simulation of Phase 1 pharmacokinetic data for deutetrabenazine and tetrabenazine.
  • the objective of the pharmacokinetic analysis was to identify an initial dosing regimen of deutetrabenazine predicted to provide exposure at steady state of the active ⁇ and ⁇ metabolites that was less than or equal to the predicted AUC at steady state of the active alpha and beta metabolites of tetrabenazine, but with a lower Cmax.
  • each of 24 healthy volunteer subjects received single doses of 25 mg of tetrabenazine and 15 mg of deutetrabenazine.
  • One of the objectives of the clinical trial was to evaluate and compare the safety of deutetrabenazine relative to tetrabenazine.
  • Subjects in the Switch cohort completed a full screening evaluation. Subjects who were eligible to enroll in the study were subsequently converted from their tetrabenazine dose regimen to a deutetrabenazine dose regimen predicted to be comparable to their existing tetrabenazine regimen. Subjects received existing tetrabenazine regimen through midnight of Day 0 and switched to their assigned deutetrabenazine regimen the next morning (Day 1 of the study). The initial dose was based on a conversion method, defined by a Phase 1 pharmacokinetic comparison of deutetrabenazine and tetrabenazine suggesting an initial dose of deutetrabenazine that is approximately 50% of the existing tetrabenazine dose (Table 15).
  • the dose of deutetrabenazine was allowed to be adjusted upward or downward once per week in increments of 6 mg/day until a dose that adequately controls chorea was identified, the subject experienced a protocol defined “clinically significant” adverse event, or the maximal allowable dose was reached.
  • the investigator in consultation with the subject and caregiver, determined when an adequate level of chorea control had been achieved. If a subject experienced a “clinically significant” adverse event attributable to deutetrabenazine, the investigator determined if a dose reduction or suspension was necessary.
  • the investigator in consultation with the subject and caregiver, determined when an adequate level of chorea control was achieved; the dose of DTBZ could be increased on a weekly basis until there was adequate control of chorea, the subject experienced a protocol defined clinically significant adverse event, or the maximal allowable dose was reached.
  • all subjects had regular contact with the study site for evaluation of safety and chorea control. Long-term treatment will continue until deutetrabenazine becomes commercially available in the U.S.
  • a total of 37 subjects with chorea associated with HD that was adequately controlled with tetrabenazine who had converted from tetrabenazine to deutetrabenazine treatment in ARC-HD Switch were included in an analysis conducted to assess maintenance of chorea control following dose conversion.
  • the subjects included in the analysis were each converted from tetrabenazine treatment to a deutetrabenazine daily dose, administered twice daily, that was approximately 30% to 50% of their prior total daily tetrabenazine dose.
  • the mean dose of TBZ at baseline was 42 mg and, after the overnight switch, the mean dose of deutetrabenazine was 20 mg.
  • Mean daily doses of deutetrabenazine following the switch from TBZ are given below in Table 15.
  • TMC Total Maximal Chores
  • TMC Total Maximal Chores
  • TMS Total Motor Score
  • FIG. 7 A summary of the change in mean chorea score observed and the mean daily dose of tetrabenazine or deutetrabenazine corresponding to the chorea score is provided in FIG. 7 .
  • TMS Total Motor Score
  • AEs Frequent treatment-emergent AEs, defined as events occurring in at least 4% of subjects across all time periods in either cohort, are summarized below in Table 21.
  • the most common AEs during the Entire Treatment Period in the Switch Cohort were fall (3 subjects, [8.1%]), somnolence (9 [24.3%], but most were transient and did not require dose adjustment), depression (8 [10.7%]), and anxiety (3 [8.1%]).
  • the types of common adverse events observed were consistent with those observed with deutetrabenazine treatment in First-HD. Falls are difficult to assess in this study population with chorea and HD; the majority of the falls were not considered to be related to study drug.
  • Safety scales were incorporated into the study design to monitor for subclinical toxicity associated with deutetrabenazine treatment. These included observed values and changes in the UHDRS, SDQ, UPDRS dysarthria question, Barnes Akathisia Rating Scale (BARS), HADS, Epworth Sleepiness Scale (ESS), Columbia Suicide Severity Rating Scale (C-SSRS), and Montreal Cognitive Assessment (MoCA ⁇ ).
  • the overall analysis of the safety scales showed no increased risk with deutetrabenazine treatment through Week 28 as of the visit cut-off date for this study. Eight Rollover patients had apparent decline in two of four cognitive measures (MoCA and the verbal fluency task) at Week 28.
  • results of this study support deutetrabenazine as an effective therapeutic option, with a favorable safety profile, for treatment of chorea associated with HD.
  • the results support the safety of an overnight switch from TBZ to a predicted AUC-matched dose of deutetrabenazine, which can be achieved without a loss of chorea control.
  • Deutetrabenazine tablets were provided in dosage strengths of 6, 9, 12, 15, and 18 mg. During dose adjustment/titration, deutetrabenazine was supplied in weekly blister cards. During long-term treatment, deutetrabenazine will be supplied in 30-count bottles. Study drug were administered as follows. All treatment regimens were administered twice daily (BID) with meals, approximately 10 hours apart during the day. The starting dose was deutetrabenazine 12 mg/day (6 mg BID) regardless of previous treatment in the parent trial. Prior treatment assignment from the parent trial remained blinded.
  • BID twice daily
  • the maximum total daily dose of deutetrabenazine was 48 mg/day (24 mg BID) unless the subject is on a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion), in which case the maximum total daily dose is 36 mg/day.
  • Daily doses up to 36 mg/day were given as one tablet BID whereas daily doses of 42 mg/day and 48 mg/day were given as two tablets BID.
  • the dose of deutetrabenazine should be increased on a weekly basis in increments of 6 mg per day until 1) there was adequate control of dyskinesia; 2) the subject experienced a protocol defined clinically significant AE (defined as related to study drug and either a) moderate or severe in intensity or b) meets the criteria for a SAE); or 3) the maximal allowable dose was reached. If a subject experienced a clinically significant AE attributable to deutetrabenazine, the Investigator determined if a dose reduction or suspension was necessary.
  • the dose of deutetrabenazine may be adjusted (upward or downward) in increments of 6 mg per day, if necessary, to optimize dyskinesia control while minimizing AEs.
  • changes in dose may not occur more frequently than once per week.
  • Subjects who successfully completed a parent study were eligible to enroll into this study after a 1-week washout period and the final evaluation. As subjects had discontinued study drug or placebo for 1 week, they underwent deutetrabenazine dose titration in this study. During titration, the investigator, in consultation with the subject determined when an adequate level of dyskinesia control had been achieved. The dose of deutetrabenazine was adjusted (upward or downward) in increments of 6 mg per day up to once per week, until adequate control of dyskinesia was achieved, a clinically significant adverse event related to study drug (either a) moderate or severe in intensity or b) a serious adverse event) occurred, or the maximal allowable dose is reached.
  • a subject experienced a clinically significant AE attributable to deutetrabenazine, the investigator determined if a dose reduction or suspension was necessary. Subjects had a telephone contact at Week 1 and a clinic visit at Week 2, to evaluate safety and establish a dose of study drug that adequately controlled dyskinesia and was well tolerated. Although subjects entered the long-term treatment period after Week 2, titration continued through Week 6 to optimize dose.
  • AEs adverse events
  • UPDS Unified Parkinson's Disease Rating Scale
  • BARS Barnes Akathisia Rating Scale
  • HDS Hospital Anxiety and Depression Scale
  • C-SSRS Columbia Suicide Severity Rating Scale
  • ESS Epworth Sleepiness Scale
  • MoCA ⁇ Montreal Cognitive Assessment
  • AIMS Abnormal Involuntary Movement Scale
  • CGIC Clinical Global Impression of Change
  • CDQ-24 modified Craniocervical Dystonia
  • Results are given in FIG. 9 , which shows that by Week 6 of the study, over 50% of subjects were much or very much improved according to PGIC and CGIC.
  • ARM-TD Aim to Reduce Movements in Tardive Dyskinesia
  • Subjects were screened for inclusion in the study as follows. Inclusion criteria included: between 18 and 75 years of age, inclusive; history of using a dopamine receptor antagonist for at least 3 months (or 1 month in subjects 60 years of age and older); clinical diagnosis of TD, and has had symptoms for at least 3 months prior to Screening; TD symptoms are bothersome to the subject or cause functional impairment; at Screening and Baseline visits, the subject has moderate or severe abnormal movements as judged by the Investigator based on Item 8 of the AIMS and a total motor AIMS score of ⁇ 6 (based on Items 1 through 7) as assessed by the Principal Investigator; for subjects with underlying psychiatric illness, subject is psychiatrically stable and has had no change in psychoactive medications (including, but not limited to neuroleptics, benzodiazepines, anticonvulsants, and mood stabilizers) for ⁇ 30 days before Screening (45 days for antidepressants); subjects on long-acting (depot) medications have been on stable therapy (dose, frequency) for ⁇ 3 months before
  • Deutetrabenazine tablets or placebo were supplied as 6, 9, 12, 15, and 18 mg tablets and administered BID with meals in the morning and evening (recommended 10 hours apart; minimum 6 hours apart). Dose suspensions of up to one week were permitted if the subject experienced a clinically significant adverse event.
  • the objectives of the study was to evaluate the efficacy of SD-809 in reducing the severity of abnormal involuntary movements associated with tardive dyskinesia and the safety and tolerability of titration and maintenance therapy with deutetrabenazine in subjects with drug-induced tardive dyskinesia.
  • the primary efficacy endpoint is the change in AIMS score (Items 1 through 7) from baseline to Week 12, as assessed by blinded central video rating.
  • Baseline AIMS score is defined for each subject as the Day 0 assessment.
  • the AIMS is composed of 12 clinician-administered and scored items. Items 1-10 are rated on a 5-point, anchored scale and consist of the following:
  • a total score from items 1 through 7 can be calculated and represent observed movements, with higher scores indicative of more severe dyskinesia.
  • Item 8 can be used as an overall severity index; items 9 and 10 provide additional information with regard to patient incapacitation and awareness; and items 11 and 12 provide information that may be useful in determining lip, jaw, and tongue movements.
  • the key secondary endpoints are: 1) the proportion of subjects who are a treatment success at Week 12, based on the Clinical Global Impression of Change (CGIC); 2) the proportion of subjects who are a treatment success at Week 12, based on the Patient Global Impression of Change (PGIC); and 3) the change in the modified Craniocervical Dystonia Questionnaire (CDQ-24) from baseline to Week 12.
  • CGIC Clinical Global Impression of Change
  • PGIC Patient Global Impression of Change
  • CDQ-24 modified Craniocervical Dystonia Questionnaire
  • the CDQ-24 was selected for use in the present study because it includes domains which are relevant not only to CD and BPS, but to TD, such as stigma, emotional well-being, pain, activities of daily living, and social/family life.
  • the CDQ-24 has been modified such that the questions focus more directly on the impact of TD (as opposed to CD/BPS) on quality of life.
  • Additional secondary endpoints included 1) the percent change in AIMS score (central rating) from baseline to Week 12; 2) based on the change in AIMS score (central rating) from baseline to Week 12, the cumulative proportion of responders for responder levels ranging from a 10% improvement from baseline to a 90% improvement from baseline in steps of 10 percentage points; and 3) Change in AIMS score (Items 1 through 7) from baseline to Week 12, as assessed by the local rater, wherein baseline AIMS score is defined for each subject as the Day 0 assessment.
  • Digital video recordings of AIMS assessments made at all clinic visits were rated by pairs of central raters who were experts in movement disorders and were blinded to treatment arm, sequence of video, and the investigator AIMS score. Analysis was carried out using a linear mixed model for repeated measurements (MMRM) with the change in the AIMS score as the dependent variable.
  • MMRM linear mixed model for repeated measurements
  • the model included fixed effects for treatment group, time point (five levels: Weeks 2, 4, 6, 9, and 12), the treatment group by time point interaction, and the randomization stratification variable.
  • the unstructured covariance model was used and the primary analysis compared the deutetrabenazine and placebo groups at Week 12 using a two-sided test at the 5% level of significance.
  • the study also showed a favorable safety and tolerability profile for deutetrabenazine, including low rates of depression, somnolence, insomnia and akathisia. Fewer patients taking deutetrabenazine than placebo experienced serious adverse events (SAEs) (4 patients [6.9%] in deutetrabenazine versus 6 [10.2%] in placebo; none of the SAEs were treatment related) or experienced adverse events leading to discontinuation (1 patient [1.7%] versus 2 patients [3.4%]).
  • SAEs serious adverse events
  • deutetrabenazine, other deuterium substituted tetrabenazines and valbenazine will be efficacious in the treatment of tardive dyskinesia and other movement disorders and symptoms, such as dyskinesias generally, dystonia, ballismus, akinesia, and parkinsonism, and that the dosing regimens and methods disclosed herein will yield significant patient benefits.
  • Tourette syndrome is a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics, which per DSM-V criteria first presents in childhood, before 18 years of age.
  • Inclusion criteria included: 12 to 18 years of age, inclusive; DSM-V diagnosis of TS and has manifested motor and phonic tics within 3 months before screening; total tic score of 19 or higher on the YGTSS; TS-CGI score of 4 or higher (consistent with moderately ill); tic severity and frequency has been stable for at least 2 weeks; able to swallow study medication whole; willing to adhere to medication regimen and to comply with all procedures; in good general health, as indicated by medical and psychiatric history as well as physical and neurological examination; written, informed consent (subject and parent/guardian); and female subjects of childbearing potential agree to use an acceptable method of contraception through study completion, including abstinence, IUD or intrauterine system in place for at least 3 months prior; subject or partner using barrier method (e.g., condom, diaphragm, or cervical cap) with spermicide; partner has a documented vasectomy >6 months prior to enrollment; stable hormonal contraception (with approved oral
  • Exclusion criteria included: serious untreated or undertreated psychiatric illness, such as depression, schizophrenia, or bipolar disorder (but subjects receiving antidepressant therapy may be enrolled if on a stable dose for at least 8 weeks before); history of suicidal thoughts or behavior, including previous intent to act on suicidal ideation with a specific plan (positive answer to question 5 on the Columbia Suicide Severity Rating Scale [C-SSRS]) irrespective of level of ambivalence at the time of suicidal thought, previous preparatory acts or behavior, or previous actual, interrupted, or aborted suicide attempt; subject has received any of the following concomitant medications within 14 days prior to screening or baseline: tetrabenazine, neuroleptics (oral or depot, typical and atypical; depot ⁇ within 3 months of screening), guanfacine or clonidine (within 7 days of screening or baseline), benzodiazepines such as clonazepam, topiramate,
  • an independent rater assessed tic severity with the Yale Global Tic Severity Scale (YGTSS) and tic impact with the TS-Clinical Global Impression (TS-CGI) scale.
  • the independent rater will not have knowledge of the subject's clinical care, including medications or reports of adverse events (AEs).
  • Study drug was available in five dose strengths: 6, 9, 12, 15, and 18 mg, all of which were identical in size, shape, and color (white). Subjects who qualified for the study were assigned to treatment with deutetrabenazine and were titrated over 6 weeks to a dose level of study drug that adequately suppressed tics and was well tolerated (i.e., optimal dose). Subjects then maintained that dose level for the duration of the treatment period. Subjects who were receiving CBIT (Comprehensive Behavioral Intervention for Tics) therapy were permitted to participate as long as therapy had been stable/ongoing for at least 4 weeks before Screening and was expected to be stable for the duration of the trial. Study drug was dosed as follows. All treatment doses were administered with meals.
  • a daily dose of 6 mg was given once a day in the morning, and daily doses of 12 mg and higher were administered twice daily in divided doses, approximately 10 hours apart during the day.
  • the starting dose was deutetrabenazine 6 mg in the AM.
  • the dose of study drug was optionally adjusted weekly in increments of 6 mg/day during the titration period to identify a dose level that suppressed tics and was well tolerated. Dose reductions were in increments of 6 mg/day.
  • the maximum total daily dose of deutetrabenazine at the Week 5 visit or later was 36 mg (18 mg twice daily [BID]).
  • subjects who met selection criteria had a comprehensive evaluation including physical and neurological examination. Subjects then underwent a baseline assessment of tic severity (performed by an independent rater) and co-morbid illnesses. Following this evaluation, subjects continuing to meet selection criteria were provided with deutetrabenazine and were instructed to start treatment on Day 1, the day after the baseline visit.
  • the YGTSS and TS-CGI were assessed by an independent rater.
  • the Investigator in consultation with the subject and parent/guardian, determined when an adequate level of tic suppression had been achieved.
  • the dose of deutetrabenazine was increased on a weekly basis until there was adequate suppression of tics, the subject experienced a protocol-defined “clinically significant” AE (defined as an AE that is related to study medication and either (1) moderate or severe in intensity or (2) meets the criteria for a serious adverse event [SAE]), or the maximal allowable dose was reached.
  • SAE serious adverse event
  • a subject experienced a “clinically significant” AE that was attributed to study drug, the Investigator used his or her judgment to determine if a dose reduction or suspension was necessary. Dose adjustments were to be made based on all available information, including the subject and parent/guardian reports of AEs and tic suppression, the clinical assessment of safety and efficacy by the Investigator, as well as information from rating scales. At the end of the titration period, the subject's dose was established for the maintenance period.
  • a PK substudy was conducted to evaluate the PK of deutetrabenazine and its metabolites in up to 9 of the 21 enrolled subjects.
  • Subjects in the PK substudy underwent sequential PK blood sampling over the course of 6 hours postdose at the Week 8 visit.
  • a single PK sample was obtained at Week 8 at the time of the blood draw for clinical laboratory tests.
  • AEs adverse events
  • C-SSRS Columbia Suicide Severity Rating Scale
  • BDI-II Beck Depression Inventory
  • CY-BOCS Children's Yale-Brown Obsessive-Compulsive Scale
  • YGTSS Yale Global Tic Severity Scale
  • TTS Total Tic Severity Score
  • GSS Global Severity Score
  • TS-CGI Tourette Syndrome Clinical Global Impression
  • TS-PGIC Tourette Syndrome Patient Global Impression of Change
  • deutetrabenazine, other deuterium substituted tetrabenazines and valbenazine will be efficacious in the treatment of Tourette syndrome and other movement disorders and symptoms, such as tics, stereotypy, akathisia, dyskinesia, and restless legs syndrome, and that the dosing regimens and methods disclosed herein will yield significant patient benefits.
  • the primary objective of this study is to evaluate the efficacy of deutetrabenazine to reduce motor and phonic tics associated with TS; the secondary objective of this study is to evaluate the safety and tolerability of titration and maintenance therapy with deutetrabenazine.
  • the study will include male and female patients between 6 and 16 years of age (inclusive) with a tic associated with Tourette syndrome (TS). Patients will be randomized and stratified by age at baseline [6 to 11 years, 12 to 16 years]).
  • the dose of study drug for each patient will be titrated to an optimal level followed by maintenance therapy at that dose.
  • the overall treatment period will be 12 weeks in duration.
  • the titration period will be 7 weeks, and the maintenance period will be 5 weeks, which will be followed by a washout period of 1 week.
  • Patients may be enrolled in the study if they meet all of the following criteria: 6 to 16 years of age, inclusive, at baseline; weight of at least 44 pounds (20 kg) at baseline; meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) diagnostic criteria for TS and, in the opinion of the investigator, patient, and caregiver/adult, the patient's active tics are causing distress or impairment; TTS of 20 or higher on the YGTSS at screening and baseline; able to swallow study medication whole; patient and caregiver/adult are willing to adhere to the medication regimen and to comply with all study procedures; good general health, as indicated by medical and psychiatric history as well as physical and neurological examination; ability to understand the nature of the study and its procedures, and expected to complete the study as designed (in investigator's opinion); written informed consent; women/girls of childbearing potential (not surgically sterile ( ⁇ 3 months)—via tubal ligation, hysterectomy, oophorectomy—or congenitally sterile) whose male partners are of
  • Patients will not be enrolled in this study if they meet any of the following criteria: neurologic disorder other than TS that could obscure the evaluation of tics; patient's predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with Autism Spectrum Disorder; confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder; clinically significant depression at screening or baseline (but patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 weeks before screening (see list below for prohibited antidepressants); history of suicidal intent or related behaviors within 2 years of screening: previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought; previous suicidal preparatory acts or behavior; history of a previous actual, interrupted, or aborted suicide attempt; a first-degree relative who has completed suicide; clinically significant OCD at baseline that, in the opinion of the investigator, is the primary cause of impairment; patient has received CBIT for TS or CBT for OCD within
  • Prohibited drugs include: azithromycin, chloroquine/Mefloquine, clarithromycina, domperidone, droperidol, erythromycina, moxifloxacin, sevoflurane, probucol, sparfloxacin, chlorpromazine, aripiprazole, haloperidol, asenapine maleate, loxapine, clozapine, molindone, iloperidone, perphenazine, lurasidone, pimozide, olanzapine, prochlorperazine, olanzapine/fluoxetine, thioridazine paliperidone, thiothixene, quetiapine, trifluoperazine, risperidone, promethazine-containing compounds, ziprasidone, and tiapride.
  • the study's primary efficacy endpoint will be the change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from baseline to week 12, with a goal of reducing motor and phonic/vocal tics.
  • Secondary efficacy endpoints will be changes in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score, Tourette Syndrome-Patient Global Impression of Severity (TS-PGIS) score, and the Gilles de la Tourette Syndrome-Quality of Life (GTS-QOL) physical/activities of daily living (ADL) subscale, all from baseline to week 12.
  • TTS Total Tic Score
  • YGTSS Yale Global Tic Severity Scale
  • GTS-QOL Gilles de la Tourette Syndrome-Quality of Life
  • Safety endpoints will be: incidence of adverse events; observed values and changes from baseline in vital signs; observed values and change from baseline in the Children's Depression Inventory 2 (CDI-2; Parent and Self-report versions); observed values in the children's Columbia Suicide Severity Rating Scale (C-SSRS); observed values in electrocardiogram (ECG) parameters and shifts from screening for clinically significant abnormal findings; and observed values and changes from screening in clinical laboratory parameters (hematology, chemistry, and urinalysis).
  • CDI-2 Children's Depression Inventory 2
  • C-SSRS Columbia Suicide Severity Rating Scale
  • ECG electrocardiogram
  • the dose of the study drug will be increased until 1) there is optimal reduction of tics, as determined by the investigator, in consultation with the patient and caregiver/adult; 2) the dose is not tolerable.
  • the patient's dose will be established for the maintenance period. Patients will continue to receive their maintenance dose over the next 5 weeks, although dose reductions for adverse events are allowed. Patients will return to the clinic at weeks 9 and 12 for assessments of safety and efficacy. At week 12, patients will undergo a complete evaluation, including safety and efficacy measures.
  • study drug will be administered as oral tablets at a starting dose of 6 mg once daily and titrated.
  • Tablets of deutetrabenazine will be available in the following dose strengths: 6, 9, 12, 15, and 18 mg, distinguishable by imprint and color.
  • Instruction will be provided to ensure that: the starting dose of 6 mg in all patients will be administered in the evening on days 1 and 2, followed by AM administration for the remainder of week 1 (if body weight is ⁇ 40 kg); study drug should be swallowed whole and taken with food; subsequent daily doses of 12 mg and higher will be administered twice daily in 2 divided doses, approximately 8 to 10 hours apart during the day; a minimum of 6 hours should elapse between doses; if a patient misses a dose, and it is within 6 hours of the next dose, the missed dose should be skipped; if patients experience insomnia while taking the initial 6-mg dose in the evening, they may switch to taking it as a morning dose for 2 days; after week 1, dose increases should not occur more frequently than every 5 days; and dose reductions, if required, should be in increments of 6 mg.
  • Patients will be randomly assigned to receive treatment with deutetrabenazine or matching placebo in a 1:1 ratio.
  • the primary objective of this study is to evaluate the safety and tolerability of long-term therapy with deutetrabenazine; the secondary objective is to evaluate efficacy.
  • the study will include male and female patients with a tic associated with Tourette syndrome (TS) who have previously completed participation in either of the above clinical studies of deutetrabenazine.
  • TS Tourette syndrome
  • Informed consent/assent will be obtained before any study procedures are performed. Patients who have been off study drug for several months at the time of enrollment, and who are stable from a medical and psychiatric standpoint, will undergo a screening evaluation as described above in the randomized study. To reduce patient burden, some data collected in the randomized study above will be used to provide corresponding data in this open label study. Patients may be rescreened at the discretion of the medical monitor. Inclusion and exclusion criteria will be similar to those discussed above for the randomized trial, with the exception that participation in either of the trials above is an inclusion, and not an exclusion, criterion, and that data regarding disqualifying DSM-V diagnoses may be obtained from the screening visit of the randomized study.
  • the baseline visit will occur simultaneously with the week 13 visit of that study. Week 13 assessments specified for that are also specified for the baseline visit of that study need not be repeated. For all patients, the baseline visit will occur on the same day as the scheduled first dose of the study drug (day 1). For patients with clinically significant laboratory abnormalities at week 12 in the randomized study above, the week 13 value will serve as baseline in this study. Rollover for such patients must be approved by the medical monitor and may be delayed.
  • the patient's initial dose for the maintenance period will be established. Dose adjustments of deutetrabenazine (upward or downward) may be made during the maintenance period, if necessary, but not more often than every 5 days and only in increments of 6 mg. Dose adjustments should be made based on all available information, including the patient and caregiver/adult reports of adverse events and tic reduction, the clinical assessment of safety and efficacy by the investigator, the patient's weight and CYP2D6 medication status, and information from the rating scales.
  • in-person (in-clinic) study visits will be scheduled at weeks 8, 15, 28, 41, and 54 for assessments of safety and efficacy. At week 54, patients will undergo a complete evaluation as above in the randomized trial.
  • Study drug will be administered as above for the randomized trial.
  • Efficacy endpoints will include the Primary and Secondary Efficacy Endpoints as above in the randomized study, with a goal of reducing severity of motor and phonic/vocal tics. Exploratory endpoints be as above in the randomized study, from baseline to each visit.
  • prolongation of the QT interval can favor the development of cardiac arrhythmias, such as torsade de pointes, which can degenerate into ventricular fibrillation and lead to death.
  • cardiac arrhythmias such as torsade de pointes
  • tetrabenazine should not be used in conjunction with agents known to prolong the QT interval.
  • the key outcome measure was to determine the effect of single doses of deutetrabenazine on the QTc interval.
  • a 50 mg dose of tetrabenazine was selected as this was the maximal dose employed in the TQT study for tetrabenazine and resulted in the Warning and Precaution in the product label.
  • a 24-mg dose of deutetrabenazine was selected as it provides comparable systemic exposure (AUC) to 50 mg of tetrabenazine, but with a lower peak concentration (Cmax).
  • ⁇ QTcF is defined as the difference between the least squares mean change from baseline for the active drug and placebo.
  • deutetrabenazine was compared with deutetrabenazine placebo (administered under fed conditions) and tetrabenazine was compared with tetrabenazine placebo (administered under fasted conditions).
  • the maximal ⁇ QTcF was observed at the 8-hour time point for deutetrabenazine and the 3-hour time point for tetrabenazine.
  • the upper limit of the 95% one-sided confidence interval is the upper limit of the 90% 2-sided confidence interval.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018170214A1 (en) 2017-03-15 2018-09-20 Zhang Chengzi Analogs of deutetrabenazine, their preparation and use
US20190374521A1 (en) * 2018-06-10 2019-12-12 Axsome Therapeutics, Inc. Methods of modulating tetrabenazine metabolites plasma levels using bupropion
WO2020123900A1 (en) 2018-12-13 2020-06-18 Auspex Pharmaceuticals, Inc. Deutetrabenazine for the treatment of dyskinesia in cerebral palsy
CN112292121A (zh) * 2018-06-10 2021-01-29 艾克萨姆治疗公司 使用安非他酮调控丁苯那嗪代谢产物血浆水平的方法
US20240238273A1 (en) * 2018-06-10 2024-07-18 Axsome Therapeutics, Inc. Methods of modulating tetrabenazine metabolites plasma levels using bupropion
WO2024166115A1 (en) 2023-02-10 2024-08-15 Teva Pharmaceutical Industries Ltd. Movement disorder detection and assessment

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9346800B2 (en) 2012-09-18 2016-05-24 Auspex Pharmaceuticals, Inc. Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
EA201791977A1 (ru) 2015-03-06 2018-01-31 Оспекс Фармасьютикалз, Инк. Способы лечения патологических непроизвольных движений
CN108473489B (zh) 2015-10-30 2022-09-02 纽罗克里生物科学有限公司 Valbenazine盐及其多晶形物
JP6869988B2 (ja) 2015-12-23 2021-05-12 ニューロクライン バイオサイエンシーズ，インコーポレイテッド （Ｓ）−（２Ｒ，３Ｒ，１１ｂＲ）−３−イソブチル−９，１０−ジメトキシ−２，３，４，６，７，１１ｂ−ヘキサヒドロ−１Ｈ−ピリド［２，１−ａ］イソキノリン−２−イル２−アミノ−３−メチルブタノエートジ（４−メチルベンゼンスルホネート）の調製のための合成方法
WO2017221169A1 (en) * 2016-06-24 2017-12-28 Lupin Limited Premixes of deutetrabenazine
WO2018140093A1 (en) 2017-01-27 2018-08-02 Obrien Christopher F Methods for the administration of certain vmat2 inhibitors
WO2018200605A1 (en) * 2017-04-26 2018-11-01 Neurocrine Biosciences, Inc. Use of valbenazine for treating levodopa-induced dyskinesia
TW201919622A (zh) 2017-09-21 2019-06-01 美商紐羅克里生物科學有限公司 高劑量戊苯那嗪（valbenazine）調配物及組合物、方法以及相關套組
AU2017435893B2 (en) 2017-10-10 2023-06-29 Neurocrine Biosciences, Inc Methods for the administration of certain VMAT2 inhibitors
US10993941B2 (en) 2017-10-10 2021-05-04 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
US11306082B2 (en) * 2017-11-08 2022-04-19 Foresee Pharmaceuticals Co., Ltd. Esters of dihydrotetrabenazine
MA53239A (fr) 2018-08-15 2022-05-04 Neurocrine Biosciences Inc Procédés d'administration de certains inhibiteurs de vmat2
CN109793745B (zh) * 2019-01-24 2021-05-25 遵义医科大学 阿司匹林在制备治疗异动症药物中的应用及其药物组合物
US10940141B1 (en) 2019-08-23 2021-03-09 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
BR112022007651A2 (pt) * 2019-10-22 2022-07-12 Shinkei Therapeutics Llc Dispositivo de distribuição transdérmica de tetrabenazina
JP2024514873A (ja) * 2021-04-15 2024-04-03 ニューロクライン バイオサイエンシーズ，インコーポレイテッド デューテトラベナジンおよびｃｙｐ２ｄ６阻害剤の併用投与のための方法
JP2024514874A (ja) * 2021-04-15 2024-04-03 ニューロクライン バイオサイエンシーズ，インコーポレイテッド ある特定のｖｍａｔ２阻害剤の投与のための方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140336386A1 (en) * 2012-09-18 2014-11-13 Auspex Pharmaceuticals, Inc. Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2

Family Cites Families (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2843591A (en) 1958-07-15 Method for preparing same
US2830993A (en) 1958-04-15 Quinolizine derivatives
US3045021A (en) 1959-09-24 1962-07-17 Hoffmann La Roche Preparation of substituted 2-oxobenzoquinolizines
HU175890B (en) 1977-06-15 1980-11-28 Chinoin Gyogyszer Es Vegyeszet Process for producing new 1,2,3,4,6,7-hexahydro-11-b-alpha-benzo-square bracket-a-square brecket closed-quinolyzine derivatives
US4543370A (en) 1979-11-29 1985-09-24 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4316897A (en) 1980-09-10 1982-02-23 Hoffmann-La Roche Inc. Method of lowering serum prolactin
US5451409A (en) 1993-11-22 1995-09-19 Rencher; William F. Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends
US6221335B1 (en) 1994-03-25 2001-04-24 Isotechnika, Inc. Method of using deuterated calcium channel blockers
AU707748B2 (en) 1994-03-25 1999-07-22 Isotechnika Inc. Enhancement of the efficacy of drugs by deuteration
EA000856B1 (ru) 1995-07-24 2000-06-26 Эли Лилли Энд Компани Способ лечения синдрома дефицита внимания/гиперактивности
US6342507B1 (en) 1997-09-05 2002-01-29 Isotechnika, Inc. Deuterated rapamycin compounds, method and uses thereof
GB9817028D0 (en) 1998-08-05 1998-09-30 Smithkline Beecham Plc Novel compounds
US7260823B2 (en) 2001-01-11 2007-08-21 Prime Research Alliance E., Inc. Profiling and identification of television viewers
US6440710B1 (en) 1998-12-10 2002-08-27 The Scripps Research Institute Antibody-catalyzed deuteration, tritiation, dedeuteration or detritiation of carbonyl compounds
DK1104760T3 (da) 1999-12-03 2003-06-30 Pfizer Prod Inc Sulfamoylheteroarylpyrazolforbindelser som anti-inflammatoriske/analgetiske midler
EP1134290A3 (en) 2000-03-14 2004-01-02 Pfizer Products Inc. Pharmacophore models for the identification of the CYP2D6 inhibitory potency of selective serotonin reuptake inhibitors
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
US20020183553A1 (en) 2000-10-19 2002-12-05 Ben-Zion Dolitzky Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
US6287599B1 (en) 2000-12-20 2001-09-11 Shire Laboratories, Inc. Sustained release pharmaceutical dosage forms with minimized pH dependent dissolution profiles
CA2409552A1 (en) 2001-10-25 2003-04-25 Depomed, Inc. Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract
TW200301101A (en) 2001-12-05 2003-07-01 Wyeth Corp Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof
TW200413273A (en) 2002-11-15 2004-08-01 Wako Pure Chem Ind Ltd Heavy hydrogenation method of heterocyclic rings
EP2535042A1 (en) 2003-06-16 2012-12-19 ANDRX Pharmaceuticals LLC. Oral sustained-release composition comprising a macrolide
EP1952824A1 (en) 2003-11-21 2008-08-06 Memory Pharmaceuticals Corporation Compositions and methods of treatment using L-type calcium channel blockers and cholinesterase inhibitors
US7367953B2 (en) 2003-11-26 2008-05-06 Ge Medical Systems Global Technology Company Method and system for determining a period of interest using multiple inputs
US20100018408A1 (en) 2004-02-06 2010-01-28 Lassota Zbigniew G Brew basket assembly and brewer
WO2005079752A2 (en) 2004-02-11 2005-09-01 Rubicon Research Private Limited Controlled release pharmaceutical compositions with improved bioavailability
GB2410947B (en) 2004-02-11 2008-09-17 Cambridge Lab Ltd Pharmaceutical compounds
WO2006053067A2 (en) 2004-11-09 2006-05-18 Prestwick Pharmaceuticals, Inc. Combination of amantadine and a tetrabenazine compound for treating hyperkinetic disorders
EP2161275A1 (en) 2005-01-19 2010-03-10 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
US8258305B2 (en) 2005-02-23 2012-09-04 Prexa Pharmaceuticals, Inc. Dopamine transporter inhibitors for use in treatment of movement disorders and other CNS indications
CA2613631A1 (en) 2005-06-23 2007-01-04 Spherics, Inc. Improved dosage forms for movement disorder treatment
US20080033011A1 (en) 2005-07-29 2008-02-07 Concert Pharmaceuticals Inc. Novel benzo[d][1,3]-dioxol derivatives
US7750168B2 (en) 2006-02-10 2010-07-06 Sigma-Aldrich Co. Stabilized deuteroborane-tetrahydrofuran complex
WO2007093450A2 (en) 2006-02-17 2007-08-23 Birds Pharma Gmbh Berolina Innovative Research & Development Services Deuterated catecholamine derivatives and medicaments comprising said compounds
KR101429302B1 (ko) 2006-05-02 2014-08-11 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 방사성 표지된 디히드로테트라베나진 유도체 및 조영제로서의 이의 용도
HU227610B1 (en) 2006-09-18 2011-09-28 Richter Gedeon Nyrt Pharmaceutical compositions containing rosuvastatin potassium
BRPI0719189A2 (pt) 2006-10-12 2018-08-14 Univ Kyushu Nat Univ Corp uso de ciclosporinas modificadas
CN101553487B (zh) 2006-11-08 2012-06-13 纽罗克里生物科学有限公司 取代的3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇化合物和与其相关的方法
US8163902B2 (en) 2006-11-21 2012-04-24 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
WO2008112278A2 (en) 2007-03-12 2008-09-18 The Trustees Of Columbia University In The City Of New York Methods and compositions for modulating insulin secretion and glucose metabolism
HUE031070T2 (en) 2007-03-15 2017-06-28 Auspex Pharmaceuticals Inc Deuterated d9-venlafaxine
US8008500B2 (en) 2007-06-08 2011-08-30 General Electric Company Intermediates useful for making tetrabenazine compounds
US9827210B2 (en) 2007-06-29 2017-11-28 Phovitreal Pty Ltd Treatment or prophylaxis of a neurological or neuropsychiatric disorders via ocular administration
US8053578B2 (en) 2007-11-29 2011-11-08 General Electric Company Alpha-fluoroalkyl dihydrotetrabenazine imaging agents and probes
US7902364B2 (en) 2007-11-29 2011-03-08 General Electric Company Alpha-fluoroalkyl tetrabenazine and dihydrotetrabenazine imaging agents and probes
WO2009124357A1 (en) 2008-04-10 2009-10-15 Malvin Leonard Eutick Fast dissolving oral formulations for critical drugs
US9012471B2 (en) 2008-04-11 2015-04-21 The Trustees Of Columbia University In The City Of New York Glucose metabolism modulating compounds
JP5207852B2 (ja) 2008-06-30 2013-06-12 三洋電機株式会社 太陽電池及びその製造方法
US11016104B2 (en) 2008-07-01 2021-05-25 Curemark, Llc Methods and compositions for the treatment of symptoms of neurological and mental health disorders
US20100018969A1 (en) 2008-07-24 2010-01-28 Feature Foods, Inc. Packaging for food products
GB2462611A (en) 2008-08-12 2010-02-17 Cambridge Lab Pharmaceutical composition comprising tetrabenazine
US20110053866A1 (en) 2008-08-12 2011-03-03 Biovail Laboratories International (Barbados) S.R.L. Pharmaceutical compositions
CN102186848B (zh) 2008-09-18 2014-11-12 奥斯拜客斯制药有限公司 囊泡单胺转运体2的苯并喹啉抑制剂
US20100113496A1 (en) 2008-09-25 2010-05-06 Auspex Pharmaceuticals, Inc. Piperidine modulators of vmat2
WO2010093434A1 (en) 2009-02-11 2010-08-19 Celgene Corporation Isotopologues of lenalidomide
JP2013501810A (ja) * 2009-08-12 2013-01-17 ヴァリーント インターナショナル（バルバドス）エスアールエル 医薬組成物
US8658236B2 (en) 2009-08-21 2014-02-25 Deuteria Beverages, Llc Alcoholic compositions having a lowered risk of acetaldehydemia
US20110206782A1 (en) 2010-02-24 2011-08-25 Auspex Pharmaceuticals, Inc. Piperidine modulators of dopamine receptor
WO2011106248A2 (en) 2010-02-24 2011-09-01 Auspex Pharmaceuticals, Inc. Trimethoxyphenyl inhibitors of tyrosine kinase
JP2013527237A (ja) 2010-06-01 2013-06-27 オースペックス・ファーマシューティカルズ・インコーポレイテッド ベンゾキノロン系ｖｍａｔ２阻害剤
US9321095B2 (en) 2010-06-30 2016-04-26 General Electric Company Apparatuses and methods for cutting porous substrates
WO2012006551A2 (en) 2010-07-08 2012-01-12 The Brigham And Women's Hospital, Inc. Neuroprotective molecules and methods of treating neurological disorders and inducing stress granules
US20130197031A1 (en) * 2010-09-03 2013-08-01 IVAX International GmbH Deuterated analogs of pridopidine useful as dopaminergic stabilizers
WO2012079022A1 (en) 2010-12-10 2012-06-14 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives
WO2012081031A1 (en) 2010-12-15 2012-06-21 Enaltec Labs Pvt. Ltd. Process for preparing tetrabenazine
PT2665477E (pt) 2011-01-20 2016-01-12 Bionevia Pharmaceuticals Inc Composições de libertação modificada de epalrestat ou de um seu derivado e métodos para a sua utilização
WO2012100202A1 (en) 2011-01-22 2012-07-26 Filippo Costanzo Dynamic 2d and 3d gestural interfaces for audio video players capable of uninterrupted continuity of fruition of audio video feeds
BR112013033318A2 (pt) 2011-06-24 2019-09-24 Directv Group Inc método e sistema para obter dados de visualização e fornecer recomendações de conteúdo em um receptor
WO2013061161A2 (en) 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl New combination therapies for treating neurological disorders
US20130143867A1 (en) 2011-12-02 2013-06-06 Sychroneuron Inc. Acamprosate formulations, methods of using the same, and combinations comprising the same
KR101362482B1 (ko) 2012-01-31 2014-02-12 한국과학기술연구원 테트라베나진과 다이하이드로테트라베나진의 제조방법
EP2827856A4 (en) 2012-03-23 2016-03-09 Cardero Therapeutics Inc COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF MUSCLE DISEASES
CN102936246A (zh) 2012-11-08 2013-02-20 江苏暨明医药科技有限公司 丁苯那嗪的合成方法
WO2014120654A1 (en) 2013-01-31 2014-08-07 Auspex Pharmaceuticals, Inc. Benzoquinolone inhibitors of vmat2
CA2925562A1 (en) 2013-09-27 2015-04-02 Auspex Pharmaceuticals, Inc. Benzoquinolone inhibitors of vmat2
WO2015077520A1 (en) 2013-11-22 2015-05-28 Auspex Pharmaceuticals, Inc. Methods of treating abnormal muscular activity
WO2015077521A1 (en) 2013-11-22 2015-05-28 Auspex Pharmaceuticals, Inc. Benzoquinoline inhibitors of vesicular monoamine transporter 2
EA201791466A1 (ru) 2013-12-03 2017-11-30 Оспекс Фармасьютикалз, Инк. Способы получения соединений бензохинолина
KR20160111999A (ko) 2014-01-27 2016-09-27 오스펙스 파마슈티칼스, 인코포레이티드 소포성 모노아민 수송체 2의 벤조퀴놀린 억제제
KR20160117596A (ko) 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
EA201791977A1 (ru) 2015-03-06 2018-01-31 Оспекс Фармасьютикалз, Инк. Способы лечения патологических непроизвольных движений
CN117915901A (zh) * 2021-04-15 2024-04-19 纽罗克里生物科学有限公司 氘代丁苯那嗪和cyp2d6抑制剂的联合施用方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140336386A1 (en) * 2012-09-18 2014-11-13 Auspex Pharmaceuticals, Inc. Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Cohen, Clinical Assessment of Tourette Syndrome and Tic Disorders, Neurosc. Biobehav. Rev., 2013, 37(6), pp. 997-1007. *
Frank, Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators, BMC Neurology, 2009, 9(62), pp. 1-10. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018170214A1 (en) 2017-03-15 2018-09-20 Zhang Chengzi Analogs of deutetrabenazine, their preparation and use
US11179386B2 (en) 2017-03-15 2021-11-23 Auspex Pharmaceuticals, Inc. Analogs of deutetrabenazine, their preparation and use
US11813232B2 (en) 2017-03-15 2023-11-14 Auspex Pharmaceuticals, Inc. Analogs of deutetrabenazine, their preparation and use
US20190374521A1 (en) * 2018-06-10 2019-12-12 Axsome Therapeutics, Inc. Methods of modulating tetrabenazine metabolites plasma levels using bupropion
CN112292121A (zh) * 2018-06-10 2021-01-29 艾克萨姆治疗公司 使用安非他酮调控丁苯那嗪代谢产物血浆水平的方法
EP3790538A4 (en) * 2018-06-10 2021-06-30 Axsome Therapeutics, Inc. METHOD OF MODULATING THE PLASMA LEVELS OF TETRABENAZINE METABOLITES USING BUPROPION
AU2019284477B2 (en) * 2018-06-10 2022-08-11 Axsome Therapeutics, Inc. Methods of modulating tetrabenazine metabolites plasma levels using bupropion
US20240238273A1 (en) * 2018-06-10 2024-07-18 Axsome Therapeutics, Inc. Methods of modulating tetrabenazine metabolites plasma levels using bupropion
WO2020123900A1 (en) 2018-12-13 2020-06-18 Auspex Pharmaceuticals, Inc. Deutetrabenazine for the treatment of dyskinesia in cerebral palsy
US11324732B2 (en) 2018-12-13 2022-05-10 Auspex Pharmaceuticals, Inc. Methods for the treatment of dyskinesia in cerebral palsy
WO2024166115A1 (en) 2023-02-10 2024-08-15 Teva Pharmaceutical Industries Ltd. Movement disorder detection and assessment

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