Methods for treating abnormal involuntary movement disorders

Abstract

To provide improved compositions, dosage regimens, and methods for the treatment of abnormal muscle activity, abnormal involuntary movements, and other related disorders. a) administering to the subject an initial daily dose of at least about 6 mg of deutetrabenazine per day; b) after about one week, determining the degree of control of abnormal involuntary movements achieved with the initial daily dose and the tolerability of the initial daily dose; c) increasing the daily dose of deutetrabenazine upward by 6 mg / day for subsequent daily doses if the abnormal involuntary movements are not reduced and the initial daily dose is tolerated; d) after about one week, optionally repeating steps b) and c), provided that the abnormal involuntary movements have abated and the daily dose of deutetrabenazine is tolerated; and e) decreasing the daily dose downward by at least 6 mg / day for subsequent daily doses if the subsequent dose is not tolerated. The above-mentioned problem is solved by providing deutetrabenazine or a composition containing deutetrabenazine for treating abnormal involuntary movements in a subject.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 129,616 filed on 6 March 2015, U.S. Provisional Patent Application No. 62 / 175,112 filed on 12 June 2015, and U.S. Provisional Patent Application No. 62 / 180,012 filed on 15 June 2015, the disclosures of which are incorporated herein by reference as if they were entirely contained herein.

[0002] Novel drug regimens for deuterium-substituted benzoquinoline compounds, as well as methods for treating abnormal involuntary movement disorders, abnormal muscle activity, motor disorders, and related conditions, are disclosed herein. [Background technology]

[0003] Motor disorders are neurological conditions that affect the speed, fluency, quality, and ease of movement. Motor disorders can be classified into two basic categories: those characterized by impaired or excessive movement (referred to as "dyskinesia" and "hyperkinesia" or "hyperkinesia," respectively), and those characterized by slowness or absence of movement (referred to as "hypokinesis," "bradykinesia," or "akikinesia"). An example of "hyperkinesia" is chorea, such as that associated with Huntington's disease (HD), while Parkinson's disease (PD) can be classified as "hypokinesis" because it is often characterized by slow, intentional movement, or even paralysis in a fixed position. Both hyperkinesia and hypokinesia can severely impact a person's quality of life and make daily tasks difficult. Furthermore, motor disorders can cause physical pain and increase the likelihood of accidents.

[0004] For example, chorea is an abnormal, involuntary, sudden movement that affects all muscle groups and can flow randomly from one area of ​​the body to another; like many abnormal involuntary movements, it is often referred to alternatively as a movement disorder. Chorea is a characteristic 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 about 70% of these patients. It is considered a serious condition by physicians, given its significant impairment of daily functioning and increased risk of injury to the patient. In its early stages, chorea can contribute to impairments in speaking, writing, and daily living activities such as eating, dressing, and bathing. In later stages, chorea can cause gait instability and poor postural control, along with an increased risk of serious injury resulting from falls or impacts with objects. The severity of chorea and Parkinson's disease has been shown to be independently related to falls in patients in the later stages of HD. Dysphagia is a component of hemodialysis and can lead to recurrent aspiration pneumonia, weight loss, and behavioral disturbances.

[0005] The American Academy of Neurology guidelines state that "Huntington's disease remains a destructive neurodegenerative disease requiring neuroprotective and symptomatic treatment" and that "treatment of chorea is an important part of Huntington's disease management." A survey of 52 international experts showed that they treat chorea for the following reasons: 88% physical injury, 81% balance disorders, 77% social isolation, and 77% work impairment. Despite these guidelines, HD patients with chorea are often not treated.

[0006] The only FDA-approved therapy in the United States for treating chorea associated with hematopoietic disorder (HD) is tetrabenazine (XENAZINE®), a VMAT2 inhibitor. Tetrabenazine reduces presynaptic concentrations of monoamines, such as dopamine, in neurons that regulate bodily movement. According to a November 2013 presentation by Lundbeck, approximately 30,000 people in the United States have HD, and approximately 200,000 individuals carry the gene and may be at risk of developing HD, but only about 4,000 patients have received this therapy. The substantial majority of patients with chorea associated with HD have not received treatment with tetrabenazine. Furthermore, based on interviews with physicians in 2011, it is estimated that the use of tetrabenazine for hyperkinetic disorders other than chorea associated with HD may account for up to half of its use, indicating that only 2,000 HD patients are receiving tetrabenazine. Furthermore, a report from Baylor College of Medicine showed that only 78 of the 349 patients with hyperkinetic disorders treated with tetrabenazine between 2006 and 2009 had chorea. Clearly, there is a substantial need for effective treatment for these disorders, and this need is only partially met by the available therapies.

[0007] In addition to chorea, impairments in overall motor symptoms also severely disrupt daily function. The National Institute of Neurological Disorders and Stroke considers the motor function assessment of the Unified Huntington's Disease Rating Scale (UHDRS) in the Total Motor Score (TMS) to be a core outcome in the assessment of HD. All currently ongoing large-scale, randomized, Phase 2b / 3 clinical trials in HD patients in the United States use UHDRS-TMS as their primary outcome measure. Significant correlations have been shown in HD patients between UHDRS-TMS and functional scales related to sleep, rest, eating, work, recreation, and past activities, as well as walking, mobility, body care and movement, social interaction, communication, physical dimensions, and psychosocial dimensions. The higher the UHDRS-TMS score, the lower the statistical likelihood of being able to perform work, manage finances, drive safely, care for children, and volunteer. For every 1-point worsening of TMS, the likelihood of being able to complete certain of these tasks decreased significantly by 5% to 10%. UHDRS-TMS is an independent predictor of functional impairment based on scales that include the 36-item Short-Form Health Survey (SF-36).

[0008] In the United States, an estimated 500,000 patients also experience tardive dyskinesia, an abnormal movement disorder characterized by involuntary, repetitive, stereotyped movements that typically manifest as rapid, excessive movements induced by certain medications, such as dopamine receptor blockers used to treat mental states, and drugs such as metoclopramide used to treat various gastrointestinal disorders. Most of these patients are managed by psychiatrists and neurologists specializing in movement disorders, and there is no FDA-approved treatment for tardive dyskinesia.

[0009] In the United States, an estimated 100,000 children have tics (abnormal involuntary movements or vocalizations) associated with Tourette syndrome, and an estimated 27% are classified as moderate to severe. The peak severity of this disorder is around 12 years old, and an estimated 13% - 22% of affected children continue to take medications for tics into adulthood. For over 30 years, few new drugs have been introduced to treat tics associated with Tourette syndrome; the two approved neuroleptics and one recently approved dopamine antagonist have been identified as having deficiencies. For example, these treatments carry the risk of causing permanent neurological deficits such as tardive dyskinesia, among other adverse events.

Prior Art Documents

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Non-licensed literature

[0011] [Non-licensed document 1] Savaniら, Neurology 2007, 68(10), page 797 [Non-licensed document 2] Kenney, Expert Review of Neurotherapeutics 2006, 6(1), pages 7~17 [Non-licensed document 3] Schwartz, Biochem. Pharmacol., 1966, 15, pages 645~655

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[0012] Therefore, improved compositions, drug regimens, and methods for treating abnormal muscle activity, abnormal involuntary movements, and other related disorders are still needed. [Means for solving the problem]

[0013] Disclosed herein are methods for treating abnormal involuntary movements in an object, a) The process of administering an initial daily dose of deuterium-substituted tetrabenazine, containing at least approximately 6 mg / day, to the subject; b) Approximately one week later, a step to determine the degree of control of abnormal involuntary movements achieved using the initial daily dose (also simply called the "degree of control") and the tolerability of the initial daily dose; c) If the degree of control over abnormal involuntary movements is insufficient and the initial daily dose is tolerable, the daily dose of deuterium-substituted tetrabenazine is increased by at least 6 mg / day in subsequent daily doses; d) If applicable, repeat steps b) and c) until the degree of control over abnormal involuntary movements is sufficient and the daily dose of deuterium-substituted tetrabenazine becomes tolerable; and e) If the subsequent dose is unacceptable, the process of reducing the daily dose downward by at least 6 mg / day from the subsequent daily dose. This method includes [something]. [Brief explanation of the drawing]

[0014] [Figure 1] This figure shows the change in mean chorea scores observed in patients receiving either deutetrabenazine or placebo from the First-HD trial. [Figure 2] This figure shows the mean change from baseline in swallowing difficulties over time (determined by questionnaire) for deutetrabenazine and placebo, demonstrating a significant improvement in swallowing with deutetrabenazine treatment. [Figure 3]This figure shows the mean change from baseline in body weight (kg) over time for dutetrabenazine and placebo from the First-HD trial. [Figure 4] Figure 4A shows the mean overall behavior score for subjects treated with deutetrabenazine compared to the placebo group, from the First-HD trial. Figure 4B shows the anxiety level for subjects treated with deutetrabenazine compared to the placebo group, from the First-HD trial. Figure 4C shows the obsessive-compulsive behavior level for subjects treated with deutetrabenazine compared to the placebo group, from the First-HD trial. [Figure 5] This figure shows the change in mean chorea score observed in patients who switched from tetrabenazine to deutetrabenazine, and the mean daily dose of tetrabenazine or deutetrabenazine corresponding to the chorea score, from the ARC-HD trial. In the figure, the asterisk (*) at week 8 indicates p=0.0252. [Figure 6] This figure shows the change in mean total exercise score observed in patients who switched from tetrabenazine to deutetrabenazine in the ARC-HD trial. [Figure 7] This figure shows the mean change from baseline in swallowing difficulties over time (determined by questionnaire) in patients who switched from tetrabenazine to deutetrabenazine, from the ARC-HD trial, and indicates a trend toward improvement in swallowing with deutetrabenazine treatment. [Figure 8] This figure shows open-label, long-term data from tardive dyskinesia trials in patients with tardive dyskinesia, representing the percentage of treated subjects who showed significant or very significant improvement on the 7-point Likert scale for Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC). [Figure 9]This figure shows the mean changes in motor, vocal cord, and combined overall tic scores in subjects treated in the Tourette syndrome pilot study, from baseline to the end of treatment at week 8 and washout at week 9. The upper line (triangle) represents the vocal cord tic score; the middle line represents the motor (square) tic score; and the lower line (diamond) represents the overall (combined motor and vocal cord) tic score. Treatment with deutetrabenazine reduced (improved) both motor and vocal cord tics. [Figure 10] This figure shows the change in the clinical global impression of Tourette Syndrome from baseline to week 8 in subjects treated in the Tourette Syndrome Pilot Study. Improvement is measured by a decrease in the TS-CGI score. [Figure 11] This figure shows the overall impression of changes in Tourette syndrome patients treated in the Tourette Syndrome Pilot Study during week 8. Improvement is measured by a positive increase in the TS-PGIC score, where, for example, 1 indicates minimal improvement, 2 indicates significant improvement, and 3 indicates very significant improvement. [Modes for carrying out the invention]

[0015] Disclosed herein are methods for treating abnormal involuntary movements in an object, a) The process of administering an initial daily dose of deuterium-substituted tetrabenazine, containing at least approximately 6 mg / day, to the subject; b) Approximately one week later, a step to determine the degree of control of abnormal involuntary movements achieved using the initial daily dose (also simply called the "degree of control") and the tolerability of the initial daily dose; c) If the degree of control over abnormal involuntary movements is insufficient and the initial daily dose is tolerable, the daily dose of deuterium-substituted tetrabenazine is increased by at least 6 mg / day in subsequent daily doses; d) If applicable, repeat steps b) and c) until the degree of control over abnormal involuntary movements is sufficient and the daily dose of deuterium-substituted tetrabenazine becomes tolerable; and e) If the subsequent dose is unacceptable, the process of reducing the daily dose downward by at least 6 mg / day from the subsequent daily dose. This method includes [something].

[0016] Furthermore, a method for treating abnormal involuntary movements in a subject, a) A step in which the subject is administered an initial daily dose of at least approximately 6 mg / day of dutetrabenazine; b) Approximately one week later, a step to determine the degree of control of abnormal involuntary movements achieved using the initial daily dose and the tolerability of the initial daily dose; c) If the abnormal involuntary movements are not alleviated and the initial daily dose is tolerable, increase the daily dose of dutetrabenazine by 6 mg / day for subsequent doses; d) After approximately one week, if the abnormal involuntary movements have been reduced and the daily dose of deutetrabenazine is tolerable, the process of repeating steps b) and c); and e) If the subsequent dose is not tolerated, the daily dose is reduced by at least 6 mg / day for each subsequent dose. Methods including this are also disclosed.

[0017] In certain embodiments, abnormal involuntary movements are caused by motor disorders.

[0018] In certain embodiments, motor disorders include sitting incapacitation, akinesia, ataxia, athetosis, ballism, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesia (e.g., paroxysmal), blepharospasm, writer's cramp (hand dystonia), laryngeal dystonia (spasmodic dysphonia), and dystonia (generalized, segmental, or localized), essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's disease, The following conditions are selected: multiple system atrophy (Shy-Drager syndrome), myoclonus, Parkinson's disease, levodopa-induced dyskinesia in Parkinson's disease, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasmodic torticollis (cervical dystonia), seizures due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, stereotypic movement disorder, stereotypic syndrome, Sydenham chorea, synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson's disease.

[0019] In certain embodiments, the movement disorder is an over-movement disorder.

[0020] In certain embodiments, the abnormal involuntary movements are selected from chorea, sitting inability, dyskinesia, tremor, and tics.

[0021] In certain embodiments, 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's syndrome.

[0022] In certain embodiments, the movement disorder is selected from Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, dystonia, and levodopa-induced dyskinesia in Parkinson's disease.

[0023] In certain embodiments, the movement disorder is selected from Huntington's disease, tardive dyskinesia, and Tourette's syndrome.

[0024] In certain embodiments, the motor disorder is Huntington's disease.

[0025] In certain embodiments, the motor impairment is chorea associated with Huntington's disease.

[0026] In certain embodiments, the absence of initial or subsequent dose reduction or cessation indicates that the dose is tolerable. In certain embodiments, tolerability is determined by an assessment of one or more target levels of depression, anxiety, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation (also known as "agitation"), irritability, immobility, tardive dyskinesia, swallowing, parkinsonism, vomiting, and nausea. In certain embodiments, if one or more of the above occur, the dose is not tolerable. In certain embodiments, if drowsiness or dizziness occurs, the dose is not tolerable.

[0027] In certain embodiments, deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer.

[0028] In certain embodiments, the initial daily dose of duetetrabenazine is about 30% to about 70% of the existing total daily dose of tetrabenazine, which provides adequate control of abnormal involuntary movements. In certain embodiments, the initial daily dose of duetetrabenazine is about 40% to about 60% of the existing total daily dose of tetrabenazine, which provides adequate control of abnormal involuntary movements. In certain embodiments, the initial daily dose of duetetrabenazine is about 45% to about 55% of the existing total daily dose of tetrabenazine, which provides adequate control of abnormal involuntary movements. In certain embodiments, the initial daily dose of duetetrabenazine is about 30% to about 50% of the existing total daily dose of tetrabenazine, which provides adequate control of abnormal involuntary movements.

[0029] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0030] In a particular embodiment, the initial daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg.

[0031] In a particular embodiment, the initial daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0032] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; The first dose is approximately 24 mg, and the second dose is approximately 24 mg; The first dose is approximately 27 mg, and the second dose is approximately 27 mg; The first dose is approximately 30 mg, and the second dose is approximately 30 mg; The first dose is approximately 33 mg, and the second dose is approximately 33 mg; The first dose is approximately 36 mg, and the second dose is approximately 36 mg; and The first dose is approximately 39 mg, and the second dose is approximately 39 mg.

[0033] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; and The first dose is approximately 24 mg, and the second dose is approximately 24 mg.

[0034] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0035] In certain embodiments, the daily dose of dutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects receiving a potent CYP2D6 inhibitor concurrently. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0036] In certain embodiments, the degree of chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0037] In certain embodiments, 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%.

[0038] In certain embodiments, motor function is improved. In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transconductive Motor Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0039] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is reduced. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0040] In certain embodiments, the treatment does not worsen equilibrium. In certain embodiments, the treatment improves equilibrium.

[0041] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0042] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0043] In certain embodiments, the treatment improves swallowing.

[0044] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0045] In certain embodiments, the treatment does not cause significant symptoms of parkinsonism or dysphagia.

[0046] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0047] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0014] to

[0045] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Two embodiments are "mutually exclusive" if, as used herein, one is defined as not being able to overlap with the other. Also provided are the use of deutetrabenazine for treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0014] to

[0045] above. Also provided are the use of deutetrabenazine in the manufacture of a drug for treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0014] to

[0045] above. Also provided are compositions comprising deutetrabenazine for treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0014] to

[0045] above.

[0048] Furthermore, a method for transferring subjects receiving an existing total daily dose of tetrabenazine for the control of abnormal involuntary movements, a) A step of administering to the subject an initial daily dose of deuterium-substituted tetrabenazine, which is approximately 30% to 70% of the existing total daily dose of tetrabenazine, and at least approximately 6 mg / day; b) A process to simultaneously discontinue the daily dose of tetrabenazine; c) Depending on the case, approximately one week later, determine the degree of control of abnormal involuntary movements achieved using the initial daily dose of deuterium-substituted tetrabenazine and the tolerability of the initial dose; d) If the degree of control of abnormal involuntary movements is equivalent to or insufficient to the control achieved when the subject was receiving tetrabenazine, and the initial dose is tolerable, the daily dose is increased by at least 6 mg / day in subsequent increments; e) Depending on the circumstances, repeat steps c) and d) until the degree of control over abnormal involuntary movements improves and the initial amount becomes tolerable; and f) In cases where the subsequent dose is unacceptable, the process involves reducing the daily dose downward by at least 6 mg / day from the subsequent daily dose. Methods including this are also provided.

[0049] Furthermore, a method for switching a subject receiving an existing daily dose of tetrabenazine for the control of abnormal involuntary movements from tetrabenazine to duetetrabenazine, a) The process of discontinuing the daily dose of tetrabenazine; b) On the following day, administer to the subject an initial daily dose of duetetrabenazine, which is approximately 30% to 70% of the existing daily dose of tetrabenazine, and at least approximately 6 mg / day; c) Approximately one week later, a step to determine the degree of control of abnormal involuntary movements achieved using the initial daily dose of deuterium-substituted tetrabenazine and the tolerability of the initial dose; d) If the degree of control of abnormal involuntary movements is equivalent to or insufficient to the control achieved when the subject was receiving tetrabenazine, and the initial dose is tolerable, the daily dose is increased by 6 mg / day increments relative to the subsequent daily dose of deutetrabenazine; e) After about one week, if applicable, repeat steps c) and d) under the condition that the abnormal involuntary movements have decreased and the amount is tolerable; and f) If the subsequent dose is not tolerable, the daily dose is reduced by 6 mg / day increments from the subsequent daily dose. Methods including this are also provided.

[0050] In certain embodiments, the initial daily dose of duetetrabenazine is about 40% to about 60% of the existing total daily dose of tetrabenazine, and is at least about 6 mg / day. In certain embodiments, the initial daily dose of duetetrabenazine is about 45% to about 55% of the existing total daily dose of tetrabenazine, and is at least about 6 mg / day. In certain embodiments, the initial daily dose of duetetrabenazine is about 30% to about 50% of the existing total daily dose of tetrabenazine, and is at least about 6 mg / day.

[0051] In certain embodiments, abnormal involuntary movements are caused by motor disorders.

[0052] In certain embodiments, motor disorders include: immobility, akinesia, ataxia, athetosis, ballism, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesia (e.g., paroxysmal), blepharospasm, writer's cramp (hand dystonia), laryngeal dystonia (spasmodic dysphonia), and dystonia (generalized, segmental, or localized), essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's disease, and multiple system atrophy. The following conditions are selected: Shy-Drager syndrome, myoclonus, Parkinson's disease, levodopa-induced dyskinesia in Parkinson's disease, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasmodic torticollis (cervical dystonia), seizures due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, stereotypic movement disorder, stereotypic syndrome, Sydenham chorea, synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson's disease.

[0053] In certain embodiments, the movement disorder is an over-movement disorder.

[0054] In certain embodiments, the abnormal involuntary movements are selected from chorea, sitting inability, dyskinesia, tremor, and tics.

[0055] In certain embodiments, 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's syndrome.

[0056] In certain embodiments, the movement disorder is selected from Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, dystonia, and levodopa-induced dyskinesia in Parkinson's disease.

[0057] In certain embodiments, the movement disorder is selected from Huntington's disease, tardive dyskinesia, and Tourette's syndrome.

[0058] In certain embodiments, the motor disorder is Huntington's disease.

[0059] In certain embodiments, the motor impairment is chorea associated with Huntington's disease.

[0060] In certain embodiments, the absence of initial or subsequent dose reduction or cessation indicates that the dose is tolerable. In certain embodiments, tolerability is determined by an assessment of one or more of the following subject levels: depression, anxiety, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation, irritability, sitability, tardive dyskinesia, swallowing, parkinsonism, vomiting, and nausea. In certain embodiments, if one or more of the above occur, the dose is not tolerable. In certain embodiments, if drowsiness or dizziness occurs, the dose is not tolerable.

[0061] In certain embodiments, deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer.

[0062] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0063] In certain embodiments, the initial daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the initial daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg. In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In a particular embodiment, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0064] In a particular embodiment, the initial daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0065] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; The first dose is approximately 24 mg, and the second dose is approximately 24 mg; The first dose is approximately 27 mg, and the second dose is approximately 27 mg; The first dose is approximately 30 mg, and the second dose is approximately 30 mg; The first dose is approximately 33 mg, and the second dose is approximately 33 mg; The first dose is approximately 36 mg, and the second dose is approximately 36 mg; and The first dose is approximately 39 mg, and the second dose is approximately 39 mg.

[0066] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; and The first dose is approximately 24 mg, and the second dose is approximately 24 mg.

[0067] In a particular embodiment, The existing total daily dose of tetrabenazine is approximately 12.5 mg, and the initial daily dose of duetetrabenazine is approximately 6 mg; The existing total daily dose of tetrabenazine is approximately 25 mg, and the initial daily dose of duetetrabenazine is approximately 12 mg; The existing total daily dose of tetrabenazine is approximately 37.5 mg, and the initial daily dose of duetetrabenazine is approximately 18 mg; The existing total daily dose of tetrabenazine is approximately 50 mg, and the initial daily dose of duetetrabenazine is approximately 24 mg; The existing total daily dose of tetrabenazine is approximately 62.5 mg, and the initial daily dose of duetetrabenazine is approximately 30 mg; The existing total daily dose of tetrabenazine is approximately 75 mg, and the initial daily dose of duetetrabenazine is approximately 36 mg; The existing total daily dose of tetrabenazine is approximately 87.5 mg, and the initial daily dose of duetetrabenazine is approximately 42 mg; or The existing total daily dose of tetrabenazine is approximately 100 mg, and the initial daily dose of duetetrabenazine is approximately 48 mg.

[0068] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0069] In certain embodiments, the daily dose of dutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects concurrently receiving a potent CYP2D6 inhibitor. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0070] In certain embodiments, chorea control is improved by a reduction of at least 0.5 points on the total maximum chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0071] In certain embodiments, 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%.

[0072] In certain embodiments, motor function is improved.

[0073] In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transmuscular Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0074] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is reduced. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0075] In certain embodiments, the treatment does not worsen the equilibrium of the subject. In certain embodiments, the treatment improves the equilibrium.

[0076] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0077] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0078] In certain embodiments, the treatment improves swallowing.

[0079] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0080] In certain embodiments, the treatment does not cause significant parkinsonism or dysphagia.

[0081] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0082] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0047] to

[0080] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of duetetrabenazine for transferring a subject receiving an existing total daily dose of tetrabenazine for the control of abnormal involuntary movements, as described herein or in any of the embodiments in paragraphs

[0047] to

[0080] above. Also provided is the use of duetetrabenazine in the manufacture of a drug for transferring a subject receiving an existing total daily dose of tetrabenazine for the control of abnormal involuntary movements, as described herein or in any of the embodiments in paragraphs

[0047] to

[0080] above. Also provided is a composition comprising duetetrabenazine for use in transferring a subject receiving an existing total daily dose of tetrabenazine for the control of abnormal involuntary movements, as described herein or in any of the embodiments in paragraphs

[0047] to

[0080] above.

[0083] Furthermore, a method for treating motor impairment in subjects including administration of a daily dose of a VMAT2 inhibitor, Chorea is reduced by at least 10%, and one or more of the following conditions are met: Motor function improves by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5 ms; Alternatively, motor function has improved by at least 10%, and one or more of the following apply: Chorea is reduced by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5ms. Methods will also be provided.

[0084] In certain embodiments, motor disorders include: immobility, akinesia, ataxia, athetosis, ballism, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesia (e.g., paroxysmal), blepharospasm, writer's cramp (hand dystonia), laryngeal dystonia (spasmodic dysphonia), and dystonia (generalized, segmental, or localized), essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's disease, and multiple system atrophy. The following conditions are selected: Shy-Drager syndrome, myoclonus, Parkinson's disease, levodopa-induced dyskinesia in Parkinson's disease, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasmodic torticollis (cervical dystonia), seizures due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, stereotypic movement disorder, stereotypic syndrome, Sydenham chorea, synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson's disease.

[0085] In certain embodiments, the movement disorder is an over-movement disorder.

[0086] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is reduced. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0087] In certain embodiments, the movement disorder is selected from Huntington's disease, tardive dyskinesia, and tics associated with Tourette's syndrome.

[0088] In certain embodiments, the motor impairment is Huntington's disease. In certain embodiments, the motor impairment is chorea. In certain embodiments, the motor impairment is chorea associated with Huntington's disease.

[0089] In certain embodiments, the motor disorder is a tic. In certain embodiments, the motor disorder is a tic associated with Tourette's syndrome.

[0090] In certain embodiments, the VMAT2 inhibitor is deuterium-substituted tetrabenazine. In certain embodiments, the deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, the duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is valvebenazine.

[0091] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0092] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0093] In a particular embodiment, the daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0094] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; The first dose is approximately 24 mg, and the second dose is approximately 24 mg; The first dose is approximately 27 mg, and the second dose is approximately 27 mg; The first dose is approximately 30 mg, and the second dose is approximately 30 mg; The first dose is approximately 33 mg, and the second dose is approximately 33 mg; The first dose is approximately 36 mg, and the second dose is approximately 36 mg; and The first dose is approximately 39 mg, and the second dose is approximately 39 mg.

[0095] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; and The first dose is approximately 24 mg, and the second dose is approximately 24 mg.

[0096] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0097] In certain embodiments, the daily dose of dutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects receiving a potent CYP2D6 inhibitor concurrently. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0098] In certain embodiments, chorea control is improved by a reduction of at least 0.5 points on the total maximum chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0099] In certain embodiments, 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%.

[0100] In certain embodiments, motor function is improved.

[0101] In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transmuscular Strength Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0102] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is improved. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0103] In certain embodiments, the treatment does not worsen the equilibrium of the subject. In certain embodiments, the treatment improves the equilibrium.

[0104] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0105] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0106] In certain embodiments, the treatment improves swallowing.

[0107] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0108] In certain embodiments, the treatment does not cause significant parkinsonism or dysphagia.

[0109] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0110] Furthermore, an embodiment described in any of the above embodiments in paragraphs

[0082] to

[0108] , Chorea is reduced by at least 10%, and two or more of the following conditions are met: Motor function improves by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5 ms; Alternatively, motor function has improved by at least 10%, and two or more of the following conditions apply: Chorea is reduced by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5ms. Embodiments are also provided.

[0111] Furthermore, an embodiment described in any of the above embodiments in paragraphs

[0082] to

[0108] , Chorea is reduced by at least 10%, and three or more of the following conditions are met: Motor function improves by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5 ms; Alternatively, motor function has improved by at least 10%, and three or more of the following conditions apply: Chorea is reduced by at least 10%; The subject's physical function improves; Swallowing improves; The equilibrium does not deteriorate; The treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, fatigue, parkinsonism, or dysphagia; and The maximum increase in QTcF is less than 5ms. Embodiments are also provided.

[0112] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0082] to

[0110] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of VMAT2 inhibitors for treating motor disorders in a subject, as described in this specification or in any of the embodiments in paragraphs

[0082] to

[0110] above. Also provided is the use of VMAT2 inhibitors in the manufacture of agents for treating motor disorders in a subject, as described in this specification or in any of the embodiments in paragraphs

[0082] to

[0110] above. Also provided is a composition comprising a VMAT2 inhibitor for use when treating a motor disorder in a subject, as described in this specification or in any of the embodiments in paragraphs

[0082] to

[0110] above.

[0113] Furthermore, a method for treating abnormal involuntary movements in a subject, a) To sufficiently reduce the abnormal involuntary movements of the subject; and b) To improve one or more of the target symptoms: anxiety, swallowing, weight, irritability, global behavior, and obsessive-compulsive behavior. A method is also provided that includes a step of administering an initial daily dose of a VMAT2 inhibitor.

[0114] In a further embodiment, the method is c) Approximately one week later, a step to determine the degree of control of abnormal involuntary movements achieved using the initial daily dose and the tolerability of the initial daily dose; d) If the degree of control of abnormal involuntary movements is insufficient and the initial daily dose is tolerable, the daily dose of deuterium-substituted tetrabenazine is increased by at least 6 mg / day in subsequent daily doses; e) If applicable, repeat steps b) and c) until the degree of control over abnormal involuntary movements is sufficient and the daily dose of deuterium-substituted tetrabenazine becomes tolerable; and f) If the subsequent dose is unacceptable, the process of reducing the daily dose downward by at least 6 mg / day from the subsequent daily dose. It also includes.

[0115] Furthermore, a method for treating abnormal involuntary movements in a subject, a) To sufficiently reduce the abnormal involuntary movements of the subject; and b) To improve one or more of the following symptoms: depression, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation, inability to sit still, parkinsonism, nausea, anxiety, dysphagia, weight gain, irritability, and obsessive-compulsive behaviors. A method is also provided that includes a step of administering a target daily dose of deutetrabenazine.

[0116] In a particular embodiment, the method is c) Approximately one week after the procedure, determine the degree of control of abnormal involuntary movements achieved using the daily dose of deutetrabenazine (initial daily dose) and the tolerability of the initial daily dose; d) If the abnormal involuntary movements are not alleviated and the initial daily dose is tolerable, the daily dose of deuterium-substituted tetrabenazine is increased by at least 6 mg / day increments thereafter; e) After one week, if applicable, steps b) and c) are repeated, provided that the abnormal involuntary movements are reduced and the daily dose of deuterium-substituted tetrabenazine is tolerable; and f) If the subsequent dose is not tolerated, the daily dose is reduced by 6 mg / day for each subsequent dose. It also includes.

[0117] In certain embodiments, abnormal involuntary movements are caused by motor disorders.

[0118] In certain embodiments, the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, tics associated with Tourette syndrome, dystonia, and levodopa-induced dyskinesia in Parkinson's disease.

[0119] In certain embodiments, the movement disorder is selected from chorea associated with Huntington's disease, tardive dyskinesia, and tics associated with Tourette's syndrome.

[0120] In certain embodiments, the motor impairment is chorea associated with Huntington's disease.

[0121] In certain embodiments, the abnormal muscle activity is a tic. In certain embodiments, the abnormal muscle activity is a tic associated with Tourette's syndrome.

[0122] In certain embodiments, the daily dose of deutetrabenazine improves one or more of the target symptoms: anxiety, swallowing, weight gain, irritability, general behavior, and obsessive-compulsive behaviors. In certain embodiments, the motor disorder is chorea associated with Huntington's disease, and the daily dose of deutetrabenazine improves one or more of the target symptoms: depression, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation, sitting incapacity, parkinsonism, nausea, anxiety, swallowing difficulties, weight gain, irritability, and obsessive-compulsive behaviors. In certain embodiments, the motor disorder is selected from tardive dyskinesia and Tourette syndrome, and the daily dose of deutetrabenazine improves one or more of the target symptoms: depression, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation, sitting incapacity, parkinsonism, nausea, anxiety, swallowing difficulties, irritability, and obsessive-compulsive behaviors.

[0123] In certain embodiments, the absence of initial or subsequent dose reduction or cessation indicates that the dose is tolerable. In certain embodiments, tolerability is determined by an assessment of one or more of the following subject levels: depression, anxiety, insomnia, drowsiness, fatigue, dizziness, restlessness, agitation, irritability, sitability, tardive dyskinesia, swallowing, parkinsonism, vomiting, and nausea. In certain embodiments, if one or more of the above occur, the dose is not tolerable. In certain embodiments, if drowsiness or dizziness occurs, the dose is not tolerable.

[0124] In certain embodiments, the VMAT2 inhibitor is deuterium-substituted tetrabenazine. In certain embodiments, the deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, the duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is valvebenazine.

[0125] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0126] In a particular embodiment, the initial daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg.

[0127] In a particular embodiment, the initial daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0128] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; The first dose is approximately 24 mg, and the second dose is approximately 24 mg; The first dose is approximately 27 mg, and the second dose is approximately 27 mg; The first dose is approximately 30 mg, and the second dose is approximately 30 mg; The first dose is approximately 33 mg, and the second dose is approximately 33 mg; The first dose is approximately 36 mg, and the second dose is approximately 36 mg; and The first dose is approximately 39 mg, and the second dose is approximately 39 mg.

[0129] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; and The first dose is approximately 24 mg, and the second dose is approximately 24 mg.

[0130] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg.

[0131] In certain embodiments, the daily dose of dutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects receiving a potent CYP2D6 inhibitor concurrently. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0132] In certain embodiments, chorea control is improved by a reduction of at least 0.5 points on the total maximum chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0133] In certain embodiments, 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%.

[0134] In certain embodiments, motor function is improved.

[0135] In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transmuscular Strength Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0136] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is improved. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0137] In certain embodiments, the treatment does not worsen the equilibrium of the subject. In certain embodiments, the treatment improves the equilibrium.

[0138] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0139] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0140] In certain embodiments, the treatment improves swallowing.

[0141] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0142] In certain embodiments, the treatment does not cause significant parkinsonism or dysphagia.

[0143] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0144] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0112] to

[0142] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of VMAT2 inhibitors for treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0112] to

[0142] above. Also provided is the use of VMAT2 inhibitors in the manufacture of agents for treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0112] to

[0142] above. Also provided is a composition comprising a VMAT2 inhibitor for use when treating abnormal involuntary movements in a subject, as described in this specification or in any of the embodiments in paragraphs

[0112] to

[0142] above.

[0145] Furthermore, a method is provided for reducing chorea and improving motor function in subjects with Huntington's disease, including the administration of a daily dose of a VMAT2 inhibitor.

[0146] In certain embodiments, the VMAT2 inhibitor is deuterium-substituted tetrabenazine. In certain embodiments, the deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, the duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is valvebenazine.

[0147] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0148] In a particular embodiment, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg.

[0149] In a particular embodiment, the daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0150] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; The first dose is approximately 24 mg, and the second dose is approximately 24 mg; The first dose is approximately 27 mg, and the second dose is approximately 27 mg; The first dose is approximately 30 mg, and the second dose is approximately 30 mg; The first dose is approximately 33 mg, and the second dose is approximately 33 mg; The first dose is approximately 36 mg, and the second dose is approximately 36 mg; and The first dose is approximately 39 mg, and the second dose is approximately 39 mg.

[0151] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is approximately 21 mg, and the second dose is approximately 21 mg; and The first dose is approximately 24 mg, and the second dose is approximately 24 mg.

[0152] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine administered to subjects receiving a potent CYP2D6 inhibitor is approximately 48 mg or less, or approximately 36 mg or less. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0153] In certain embodiments, chorea control is improved by a reduction of at least 0.5 points on the total maximum chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0154] In certain embodiments, 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%.

[0155] In certain embodiments, motor function is improved.

[0156] In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transmuscular Strength Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0157] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is improved. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0158] In certain embodiments, the treatment does not worsen the equilibrium of the subject. In certain embodiments, the treatment improves the equilibrium.

[0159] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0160] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0161] In certain embodiments, the treatment improves swallowing.

[0162] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0163] In certain embodiments, the treatment does not cause significant parkinsonism or dysphagia.

[0164] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0165] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0144] to

[0163] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of VMAT2 inhibitors for improving chorea and motor function in subjects with Huntington's disease, as described in this specification or in any of the embodiments in paragraphs

[0144] to

[0163] . Also provided is the use of VMAT2 inhibitors in the manufacture of agents for improving chorea and motor function in subjects with Huntington's disease, as described in this specification or in any of the embodiments in paragraphs

[0144] to

[0163] . Also provided is a composition comprising a VMAT2 inhibitor for use in improving chorea and motor function in subjects with Huntington's disease, as described in this specification or in any of the embodiments in paragraphs

[0144] to

[0163] .

[0166] Also provided are methods for improving motor function in subjects with Huntington's disease, tardive dyskinesia, or Tourette syndrome, including administration of an approximately daily dose of a VMAT2 inhibitor. In certain embodiments, the VMAT2 inhibitor is deuterium-substituted tetrabenazine.

[0167] In certain embodiments, the subject has Huntington's disease. In certain embodiments, the subject has tardive dyskinesia. In certain embodiments, the subject has Tourette's syndrome.

[0168] In certain embodiments, deuterium-substituted tetrabenazine is duetetrabenazine. In certain embodiments, duetetrabenazine is the positive isomer of duetetrabenazine. In certain embodiments, the positive isomer of duetetrabenazine is the alpha isomer. In certain embodiments, the VMAT2 inhibitor is the positive isomer of tetrabenazine. In certain embodiments, the positive isomer of tetrabenazine is the alpha isomer.

[0169] In certain embodiments, the VMAT2 inhibitor is valbenazine.

[0170] In certain embodiments, the daily dose of deutetrabenazine is administered in one or two doses.

[0171] In a particular embodiment, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg.

[0172] In a particular embodiment, the daily dose of deutetrabenazine is administered in two doses, consisting of a first dose and a second dose.

[0173] In a particular embodiment, The first dose is approximately 6 mg, and the second dose is approximately 6 mg; The first dose is approximately 9 mg, and the second dose is approximately 9 mg; The first dose is approximately 12 mg, and the second dose is approximately 12 mg; The first dose is approximately 15 mg, and the second dose is approximately 15 mg; The first dose is approximately 18 mg, and the second dose is approximately 18 mg; The first dose is about 21 mg and the second dose is about 21 mg; The first dose is about 24 mg and the second dose is about 24 mg; The first dose is about 27 mg and the second dose is about 27 mg; The first dose is about 30 mg and the second dose is about 3 mg; The first dose is about 33 mg and the second dose is about 33 mg; The first dose is about 36 mg and the second dose is about 36 mg; and The first dose is about 39 mg and the second dose is about 39 mg.

[0174] In certain embodiments, The first dose is about 6 mg and the second dose is about 6 mg; The first dose is about 9 mg and the second dose is about 9 mg; The first dose is about 12 mg and the second dose is about 12 mg; The first dose is about 15 mg and the second dose is about 15 mg; The first dose is about 18 mg and the second dose is about 18 mg; The first dose is about 21 mg and the second dose is about 21 mg; and The first dose is about 24 mg and the second dose is about 24 mg.

[0175] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects concurrently receiving a potent CYP2D6 inhibitor. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.

[0176] In certain embodiments, chorea control is improved by a reduction of at least 0.5 points on the total maximum chorea (TMC) score. In certain embodiments, the reduction in the TMC score is at least 1 point. In certain embodiments, the reduction in the TMC score is at least 1.5 points. In certain embodiments, the reduction in the TMC score is at least 2.0 points. In certain embodiments, the reduction in the TMC score is at least 2.5 points. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 8.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 10.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.0. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 12.7. In certain embodiments, the improvement is at least above a pre-treatment "baseline" TMC score of 14.0.

[0177] In certain embodiments, 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%.

[0178] In certain embodiments, motor function is improved.

[0179] In certain embodiments, motor function is improved by a decrease of at least 1 point on the Transmuscular Strength Score (TMS). In certain embodiments, the decrease in the TMS score is at least 2 points. In certain embodiments, the decrease in the TMS score is at least 3 points. In certain embodiments, the decrease in the TMS score is at least 4 points.

[0180] In certain embodiments, dystonia is improved. In certain embodiments, gait is improved. In certain embodiments, postural instability is improved. In certain embodiments, the treatment alleviates symptoms of parkinsonism.

[0181] In certain embodiments, the treatment does not worsen the equilibrium of the subject. In certain embodiments, the treatment improves the equilibrium.

[0182] In certain embodiments, the subject is significantly improved on the PGIC scale. In certain embodiments, the subject is very significantly improved on the PGIC scale. In certain embodiments, the subject is significantly improved on the CGIC scale. In certain embodiments, the subject is very significantly improved on the CGIC scale. In certain embodiments, the subject is significantly improved on both the PGIC and CGIC scales. In certain embodiments, the subject is very significantly improved on both the PGIC and CGIC scales.

[0183] In certain embodiments, the treatment improves physical function. In certain embodiments, the subject's physical function improves when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves from baseline when measured using the SF-36 Physical Function Scale. In certain embodiments, the subject's physical function improves compared to an untreated subject when measured using the SF-36 Physical Function Scale.

[0184] In certain embodiments, the treatment improves swallowing.

[0185] In certain embodiments, the treatment does not cause a significant increase in insomnia, depression, anxiety, restlessness, suicidal ideation, inability to sit still, irritability, or fatigue.

[0186] In certain embodiments, the treatment does not cause significant parkinsonism or dysphagia.

[0187] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0188] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0165] to

[0186] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of deutetrabenazine or a VMAT2 inhibitor to improve motor function in subjects having Huntington's disease, tardive dyskinesia, or Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0165] to

[0186] . Also provided is the use of deutetrabenazine or a VMAT2 inhibitor in the manufacture of a drug for improving motor function in subjects having Huntington's disease, tardive dyskinesia, or Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0165] to

[0186] . Also provided are compositions comprising deutetrabenazine or a VMAT2 inhibitor for use in improving motor function in subjects having Huntington's disease, tardive dyskinesia, or Tourette syndrome, as described in any of the embodiments described herein or in paragraphs

[0165] to

[0186] .

[0189] Furthermore, a method for reducing motor tics or vocal tics in subjects with Tourette syndrome is also provided, which involves administering approximately a daily dose of deutetrabenazine.

[0190] In certain embodiments, the tic is a motor tic.

[0191] In certain embodiments, the tic is an articulated tic.

[0192] In certain embodiments, 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.

[0193] In certain embodiments, the daily dose of deutetrabenazine is from about 6 mg to about 48 mg. In certain embodiments, the daily dose of deutetrabenazine is selected 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 dose of deutetrabenazine administered is about 48 mg or less, or about 36 mg or less, for subjects also receiving a strong CYP2D6 inhibitor concurrently. In certain embodiments, the strong CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, sinacalcet, and ritonavir. In certain embodiments, the strong CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0194] In certain embodiments, the daily dose of deutetrabenazine is administered with food.

[0195] In certain embodiments, the daily dose of deutetrabenazine is divided into at least two doses.

[0196] In certain embodiments, the daily dose of deutetrabenazine is administered as two equal doses consisting of a first dose and a second dose.

[0197] In certain embodiments, motor or phonic tics are reduced by 25% or more when measured by the total tic score of the Yale Global Tic Severity Scale.

[0198] In certain embodiments, motor tics or vocal tics are reduced by 2 points or more on the Clinical General Impression (TS-CGI) scale for Tourette syndrome.

[0199] In certain embodiments, motor tics or vocal tics are reduced by 1 point or more on the General Stress Index (TS-PGIS) for Tourette syndrome patients. In certain embodiments, motor tics or vocal tics are reduced by 2 points or more on the General Stress Index (TS-PGIS) for Tourette syndrome patients.

[0200] In certain embodiments, the mitigation lasts for at least two weeks from baseline.

[0201] In certain embodiments, the reduction lasts for at least 4 weeks from baseline. In certain embodiments, the reduction lasts for at least 8 weeks from baseline. In certain embodiments, the reduction lasts for at least 12 weeks from baseline.

[0202] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0188] to

[0200] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of deutetrabenazine or a VMAT2 inhibitor to reduce motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0188] to

[0200] above. Also provided is the use of deutetrabenazine or a VMAT2 inhibitor in the manufacture of a drug for reducing motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0188] to

[0200] above. Also provided is a composition comprising deutetrabenazine or a VMAT2 inhibitor for use in reducing motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0188] to

[0200] above.

[0203] Furthermore, a method for reducing motor or vocal tics in subjects with Tourette syndrome is also provided, which involves administering approximately daily doses of deutetrabenazine.

[0204] In certain embodiments, the daily dose of duetetrabenazine is approximately 6 mg to approximately 48 mg. In certain embodiments, the daily dose of duetetrabenazine is approximately 6 mg to approximately 48 mg. In certain embodiments, the daily dose of duetetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg. In certain embodiments, the daily dose of duetetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects concurrently receiving a potent CYP2D6 inhibitor. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In certain embodiments, the potent CYP2D6 inhibitor is selected from paroxetine, fluoxetine, and bupropion.

[0205] In certain embodiments, the daily dose of dutetrabenazine is administered with food.

[0206] In a particular embodiment, the daily dose of deutetrabenazine is divided into at least two doses.

[0207] In a particular embodiment, the daily dose of deutetrabenazine is administered in two equal doses, consisting of a first dose and a second dose.

[0208] In certain embodiments, the target age is 6 to 16 years old. In certain embodiments, the target age is 12 to 18 years old. In certain embodiments, the target age is 6 to 18 years old.

[0209] In certain embodiments, motor and vocal tics are reduced by 25% or more, as measured by the combined tic score on the Yale Global Tic Severity Scale.

[0210] In certain embodiments, motor tics or vocal tics are reduced by two or more points in the overall clinical impression of Tourette syndrome.

[0211] In certain embodiments, the reduction is at least two weeks from baseline. In certain embodiments, the reduction is at least four weeks from baseline. In certain embodiments, the reduction is at least eight weeks from baseline. In certain embodiments, the reduction is at least twelve weeks from baseline.

[0212] In certain embodiments, deutetrabenazine is the positive isomer of deutetrabenazine. In certain embodiments, the positive isomer of deutetrabenazine is the alpha isomer.

[0213] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0214] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0202] to

[0212] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of deutetrabenazine or a VMAT2 inhibitor to reduce motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0202] to

[0212] . Also provided is the use of deutetrabenazine or a VMAT2 inhibitor in the manufacture of a drug for reducing motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0202] to

[0212] . Also provided is a composition comprising deutetrabenazine or a VMAT2 inhibitor for use in reducing motor or vocal tics in subjects with Tourette syndrome, as described in this specification or in any of the embodiments in paragraphs

[0202] to

[0212] .

[0215] Also provided is a method for reducing tic severity in subjects with Tourette syndrome, as measured by the General Impression of Severity (TS-PGIS) of the subject's Tourette syndrome, including administration of an approximately daily dose of deutetrabenazine. In a particular embodiment, the method includes a) administering a daily dose of deutetrabenazine; and b) assessing tic severity using TS-PGIS at least once every four weeks. In a further embodiment, the method further includes c) after assessing tic severity using TS-PGIS, increasing the daily dose of deutetrabenazine by at least 6 mg / day if the daily dose is tolerable; d) repeating steps b) and c) until the TS-PGIS no longer decreases further or the daily dose of deutetrabenazine is tolerable; and e) if the subsequent dose is not tolerable, decreasing the daily dose of deutetrabenazine by 6 mg / day.

[0216] In certain embodiments, the tic is a motor tic.

[0217] In certain embodiments, the tic is an articulated tic.

[0218] In certain embodiments, the target age is 6 to 16 years old. In certain embodiments, the target age is 12 to 18 years old. In certain embodiments, the target age is 6 to 18 years old.

[0219] In certain embodiments, the daily dose of deutetrabenazine is 6 mg to 48 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, and approximately 48 mg. In certain embodiments, the daily dose of deutetrabenazine is administered with food.

[0220] In certain embodiments, the severity of tics is assessed using TS-PGIS at least every two weeks. In certain embodiments, the severity of tics is assessed using TS-PGIS at least every week. In certain embodiments, the severity of tics is assessed using TS-PGIS at least every month. In certain embodiments, the severity of tics is assessed using TS-PGIS at least every three months.

[0221] In a particular embodiment, the daily dose of dutetrabenazine is divided into two doses.

[0222] In certain embodiments, the decline is at least 2 weeks from baseline. In certain embodiments, the decline is at least 4 weeks from baseline. In certain embodiments, the decline is at least 8 weeks from baseline. In certain embodiments, the decline is at least 12 weeks from baseline.

[0223] In certain embodiments, deutetrabenazine is the positive isomer of deutetrabenazine. In certain embodiments, the positive isomer of deutetrabenazine is the alpha isomer.

[0224] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0225] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0214] to

[0223] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of deutetrabenazine to reduce the severity of tics as measured by the General Sentiment-Perceived Phenomenon (TS-PGIS) of a target Tourette syndrome patient, as described herein or in any of the embodiments described above in paragraphs

[0214] to

[0223] . Also provided is the use of deutetrabenazine in the manufacture of reducing the severity of tics as measured by the General Sentiment-Perceived Phenomenon (TS-PGIS) of a target Tourette syndrome patient, as described herein or in any of the embodiments described above in paragraphs

[0214] to

[0223] . Also provided is a composition containing deutetrabenazine for use in reducing the severity of tics as measured by the General Sentiment-Perceived Phenomenon (TS-PGIS) of a target Tourette syndrome patient, as described herein or in any of the embodiments described above in paragraphs

[0214] to

[0223] .

[0226] Also provided is a method for maintaining control of abnormal involuntary movements in human subjects with motor impairment, comprising the step of administering a therapeutically effective daily dose of deutetrabenazine to a subject for a period of time sufficient to perform one or more of the following: reduce chorea by at least 10%; improve motor function by at least 10%; improve physical function; improve swallowing; improve balance; reduce abnormal involuntary movements in subjects with tardive dyskinesia; reduce motor tics; reduce vocal / articulation tics; reduce motor and vocal / articulation tics; reduce impairment in subjects with Tourette syndrome; reduce the severity of Tourette syndrome; reduce the overall impression of the patient's severity in subjects with Tourette syndrome; and greatly or very greatly improve the overall clinical impression of the patient's changes.

[0227] In certain embodiments, the disorder is selected from Huntington's disease, tardive dyskinesia, and Tourette's syndrome.

[0228] In a particular embodiment, improvement in each of the above evaluation items is measured as follows: reduction of chorea is measured by the Unified Huntington's Disease Rating Scale (UHDRS) or its subscales; reduction of chorea is measured by the Total Maximum 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 function is measured by the SF-36 Physical Function Scale; improvement in swallowing is measured by the Swallowing Difficulty Questionnaire (SDQ); improvement in balance is measured by the Berg Balance Test. The reduction of abnormal involuntary movements in subjects with tardive dyskinesia is measured by the Test (BBT); the reduction of motor tics in subjects with Tourette syndrome is measured by the YGTSS MTSS; the reduction of vocal / articulation tics in subjects with Tourette syndrome is measured by the YGTSS VTSS; the reduction of overall (motor and vocal / articulation) tics is measured by the YGTSS TTS; the reduction of disability is measured by the YGTSS disability score; the decrease in the severity of Tourette syndrome is measured by the YGTSS global severity score; and the decrease in the overall impression of the patient's severity in subjects with Tourette syndrome is measured by the TS-PGIS.

[0229] In certain embodiments, the daily dose of deutetrabenazine is approximately 6 mg to approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine is selected from approximately 6 mg, approximately 12 mg, approximately 18 mg, approximately 24 mg, approximately 30 mg, approximately 36 mg, approximately 42 mg, approximately 48 mg, approximately 54 mg, approximately 60 mg, approximately 66 mg, approximately 72 mg, and approximately 78 mg. In certain embodiments, the daily dose of deutetrabenazine administered is approximately 48 mg or less, or approximately 36 mg or less, for subjects concurrently receiving a potent CYP2D6 inhibitor. In certain embodiments, the potent CYP2D6 inhibitor is selected from fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and ritonavir.

[0230] In certain embodiments, a sufficient period is at least 4 weeks. In certain embodiments, a sufficient period is at least 8 weeks. In certain embodiments, a sufficient period is at least 12 weeks.

[0231] In certain embodiments, the reduction or improvement in the relevant scale or multiple scales is at least 10% above the baseline. In certain embodiments, the reduction or improvement in the relevant scale or at least one scale is at least 20% above the baseline. In certain embodiments, the reduction or improvement in the relevant scale or at least one scale is at least 30% above the baseline. In certain embodiments, the reduction or improvement in the relevant scale or at least one scale is at least 40% above the baseline. In certain embodiments, the reduction or improvement in the relevant scale or at least one scale is at least 50% above the baseline.

[0232] In certain embodiments, the disorder is Huntington's disease. In certain embodiments, the abnormal involuntary movements are chorea associated with Huntington's disease.

[0233] In certain embodiments, the disorder is tardive dyskinesia.

[0234] In certain embodiments, the disorder is Tourette's syndrome. In certain embodiments, the abnormal involuntary movement is a tic associated with Tourette's syndrome.

[0235] In certain embodiments, deutetrabenazine is the positive isomer of deutetrabenazine. In certain embodiments, the positive isomer of deutetrabenazine is the alpha isomer.

[0236] In certain embodiments, 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 maximum increase in QTcF is less than 5 ms.

[0237] Furthermore, embodiments are provided in which any embodiment in paragraphs

[0225] to

[0235] above can be combined with one or more of these embodiments, provided that the combinations are not mutually exclusive. Also provided is the use of deutetrabenazine for maintaining control of abnormal involuntary movements in human subjects with motor impairments, as described in this specification or in any of the embodiments in paragraphs

[0225] to

[0235] above. Also provided is the use of deutetrabenazine in the manufacture of a drug for maintaining control of abnormal involuntary movements in human subjects with motor impairments, as described in this specification or in any of the embodiments in paragraphs

[0225] to

[0235] above. Also provided is a composition comprising deutetrabenazine for maintaining control of abnormal involuntary movements in human subjects with motor impairments, as described in this specification or in any of the embodiments in paragraphs

[0225] to

[0235] above.

[0238] composition 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), p. 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), pp. 7-17). Tetrabenazine undergoes extensive oxidative metabolism, including O-demethylation of the methoxy group and hydroxylation of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, pp. 645-655). Adverse effects associated with tetrabenazine administration include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, restlessness, confusion, orthostatic hypotension, nausea, dizziness, depression, and parkinsonism.

[0239] [ka]

[0240] Deuterium-enriched tetrabenazine analog d6-tetrabenazine (equivalent to deutetrabenazine, SD-809, or DTBZ) is a deuterated analog of tetrabenazine currently in clinical development. U.S. Patent No. 8,524,733, U.S. Patent Application Publication No. 20100130480, and U.S. Patent Application Publication No. 20120003330.

[0241] [ka]

[0242] In all methods and compositions disclosed herein using deutetrabenazine, deutetrabenazine can be administered or formulated as part of a pharmaceutical composition in which the composition is deuterium-concentrated by at least 90% at each of the positions designated as D. In certain embodiments, the composition is deuterium-concentrated by at least 95% at each of the positions designated as D. In certain embodiments, the composition is deuterium-concentrated by at least 98% at each of the positions designated as D.

[0243] In humans, d6-tetrabenazine is rapidly and extensively converted in the liver to major active dihydrotetrabenazine (HTBZ) metabolites called d6-α-HTBZ and d6-β-HTBZ (as a mixture of + and - isomers), which have the following structures (showing + isomers) (similar to non-isotope-enriched tetrabenazine). These metabolites are thought to induce clinical efficacy.

[0244] [ka]

[0245] Deuterium-substituted tetrabenazines include, in addition to the deutetrabenazines disclosed above, compounds disclosed in U.S. Patent No. 8,524,733, U.S. Patent Application Publication No. 20100130480, and U.S. Patent Application Publication No. 20120003330, and PCT / US2014 / 066740 filed on November 14, 2014. Examples of such compounds are given in the following structural formulas.

[0246] In a particular embodiment of the present invention, the compound is defined by structural formula I:

[0247] [ka]

[0248] or its salts, solvates, or prodrugs (In the formula, R1 to R 27 is independently selected from the group consisting of hydrogen and deuterium; and R1 to R 27 (at least one of which is deuterium) has.

[0249] In certain embodiments, Formula I may comprise a single enantiomer, a mixture of the (+)-enantiomer and the (-)-enantiomer, a mixture of at least about 90% by weight of the (-)-enantiomer and at most about 10% by weight of the (+)-enantiomer, a mixture of at least about 90% by weight of the (+)-enantiomer and at most about 10% by weight of the (-)-enantiomer, individual diastereomers, or a mixture of its diastereomers.

[0250] In certain embodiments of the present invention, the compound has the structural formula II:

[0251]

Chemical formula

[0252] <00000> or a salt thereof (wherein R 28 to R 46 and R 48 to R 56 are independently selected from the group consisting of hydrogen and deuterium; R 47 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 substituted with one or more substituents selected from the group consisting of -NH-C(NH)NH2, -CO2H, -CO2-alkyl, -SH, -C(O)NH2, -NH2, phenyl, -OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and the R 46 substituent may be further substituted with deuterium; R 28 to R 56At least one of them is deuterium or contains deuterium. It has.

[0253] In certain embodiments, the compound of formula II has alpha stereochemistry.

[0254] In further embodiments, the compound of formula II has beta stereochemistry.

[0255] In further embodiments, the compound of formula II is a mixture of an alpha stereoisomer and a beta stereoisomer. In further embodiments, the alpha / beta stereoisomer ratio 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. In further embodiments, the beta / alpha stereoisomer ratio 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.

[0256] In a particular embodiment, R 50 ~R 56 If it is deuterium, then R1~R 49 At least one of them is deuterium.

[0257] In a particular embodiment of the present invention, the compound is defined by structural formula III:

[0258] [ka]

[0259] or its salts, stereoisomers, or racemic mixtures. (In the formula, R 57 ~R 83 is independently selected from the group consisting of hydrogen and deuterium; and R 57 ~R 83(At least one of them is deuterium.) It has.

[0260] In a particular embodiment of the present invention, the compound is structural formula IV:

[0261] [ka]

[0262] or its salt, diastereomer, or mixture of diastereomers (In the formula, R 84 ~R 110 is independently selected from the group consisting of hydrogen and deuterium; and R 84 ~R 110 (At least one of them is deuterium.) It has.

[0263] Deuterium-substituted tetrabenazine metabolites include, in addition to d6-α-HTBZ and d6-β-HTBZ disclosed above, the compounds disclosed in the following structural formulas.

[0264] The terms “alpha-dihydrotetrabenazine,” “α-dihydrotetrabenazine,” or the terms “alpha” or “alpha stereoisomer,” or the symbol “α,” applied to dihydrotetrabenazine, refer to any of the dihydrotetrabenazine stereoisomers, or mixtures thereof, having the structural formulas shown below:

[0265] [ka]

[0266] The terms "alpha" or "alpha stereoisomer" or the symbol "α" applied to compounds of formula II refer to any of the stereoisomers of the compounds of formula II shown below, or a mixture thereof:

[0267] [ka]

[0268] The terms “beta-dihydrotetrabenazine,” “β-dihydrotetrabenazine,” or the terms “beta” or “beta stereoisomer,” or the symbol “β,” applied to dihydrotetrabenazine, refer to any of the dihydrotetrabenazine stereoisomers, or mixtures thereof, having the structural formulas shown below:

[0269] [ka]

[0270] The terms "beta" or "beta stereoisomer" or the symbol "β" applied to compounds of formula II refer to any of the stereoisomers of the compounds of formula II shown below, or a mixture thereof:

[0271] [ka]

[0272] The terms "3S,11bS enantiomer" or "3R,11bR enantiomer" refer to either of the d6-tetrabenazine M4 metabolite stereoisomers having the following structural formulas:

[0273] [ka]

[0274] In certain embodiments, the chemical structure may be described as either the 3S,11bS enantiomer or the 3R,11bR enantiomer, although the text of this specification may also indicate that it is intended to describe the 3S,11bS enantiomer, the 3R,11bR enantiomer, a racemic mixture thereof, or all of the above.

[0275] The terms "(3S,11bS)-enantiomer" or "(3R,11bR)-enantiomer" applied to compounds of formula I refer to either of the stereoisomers of compounds of formula III shown below:

[0276] [ka]

[0277] The term "mixture of diastereomers" refers to any of the d6-tetrabenazine M1 metabolite stereoisomers having the following structural formulas:

[0278] [ka]

[0279] In certain embodiments, the chemical structure may be described as one of the diastereomers shown above, but the text of this specification may also indicate that it is intended to describe each individual diastereomer or a mixture thereof, or all of the above.

[0280] The term "mixture of diastereomers" applied to compounds of formula IV refers to a mixture of stereoisomers of the compound of formula IV shown below:

[0281] [ka]

[0282] Further deuterium-enriched tetrabenazine analogs include those 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]isoquinoline-2-yl2-amino-3-methylbutanoate) is a VMAT2 inhibitor. Valbenazine is currently under investigation for the treatment of movement disorders, including tardive dyskinesia. WO2008058261; WO2011153157; and U.S. Patent No. 8,039,627. Valbenazine, the valine ester of (+)-α-dihydrotetrabenazine, is slowly hydrolyzed in humans to (+)-α-dihydrotetrabenazine, the active metabolite of tetrabenazine currently used to treat Huntington's disease. Savani et al., Neurology 2007, 68(10), p. 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), pp. 7-17.

[0283] [ka]

[0284] Dihydrotetrabenazine, formed by the hydrolysis of the valine ester of barbenazine, undergoes extensive oxidative metabolism, including O-demethylation of the methoxy group and hydroxylation of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, pp. 645-655). Potentially associated adverse effects with barbenazine administration include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, restlessness, confusion, orthostatic hypotension, nausea, dizziness, depression, and parkinsonism.

[0285] Examples of deuterium-substituted analogs of valbenazine include those disclosed in WO2014120654. An example of such a compound is given by the following formula.

[0286] In a particular embodiment of the present invention, the compound is defined by structural formula I:

[0287] [ka]

[0288] or its salt (In the formula, R1~R 19 and R 21 ~R 29 It is independently selected from the group consisting of hydrogen and deuterium; R 20 These are hydrogen, deuterium, -C(O)O-alkyl and -C(O)-C 1~6 Selected from the group consisting of alkyl groups or groups that can be cleaved under physiological conditions, where the alkyl group or C 1~6 The alkyl group may be substituted with one or more substituents selected from the group consisting of -NH-C(NH)NH2-, -CO2H, -CO2alkyl, -SH, -C(O)NH2, -NH2, phenyl, -OH, 4-hydroxyphenyl, imidazolyl, and indolyl, R 20 The substituents may be further substituted with deuterium; R1~R 29 At least one of them is deuterium or contains deuterium. It has.

[0289] In certain embodiments, the compound of formula V has (+)-alpha stereochemistry.

[0290] In certain embodiments, the compound of formula V has (-)-alpha stereochemistry.

[0291] In further embodiments, the compound of formula V has (+)-beta stereochemistry.

[0292] In further embodiments, the compound of formula V has (-)-beta stereochemistry.

[0293] In further embodiments, the compound of formula I is a mixture of an alpha stereoisomer and a beta stereoisomer. In further embodiments, the alpha / beta stereoisomer ratio 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. In further embodiments, the beta / alpha stereoisomer ratio 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.

[0294] In a particular embodiment, the structural formula VI is disclosed herein:

[0295] [ka]

[0296] or its salt or stereoisomer (In the formula, R1~R 19 and R 21 ~R 39 It is independently selected from the group consisting of hydrogen and deuterium; R1~R 19 and R 21 ~R 39 (At least one of them is deuterium.) It is a compound of [the compound].

[0297] In a particular embodiment of the present invention, the compound is defined by structural formula VII:

[0298] [ka]

[0299] or its salt or stereoisomer (In the formula, R 20 -C(O)O-alkyl and -C(O)-C 1~6Selected from the group consisting of alkyl groups or groups that can be cleaved under physiological conditions, where the alkyl group or C 1~6 The alkyl group may be substituted with one or more substituents selected from the group consisting of -NH-C(NH)NH2, -CO2H, -CO2alkyl, -SH, -C(O)NH2, -NH2, phenyl, -OH, 4-hydroxyphenyl, imidazolyl, and indolyl, R 20 (The substituents may be further substituted with deuterium.) It has.

[0300] Furthermore, the compounds disclosed herein are not limited to those with respect to carbon. 13 C or 14 Regarding C and sulfur 33 S, 34 S, or 36 Regarding S and nitrogen 15 For N and oxygen 17 O or 18 It may contain less common isotopes of other elements, such as oxygen (O).

[0301] Deuterium kinetic isotope effect Deuterium (D) is a naturally occurring, non-radioactive, stable isotope of hydrogen (H) that contains both a proton and a neutron in its nucleus. The presence of the neutron doubles the mass of D compared to H, and subsequently increases the vibrational frequency of the CD covalent bond compared to the CH covalent bond. This increase in the vibrational frequency of the covalent bond leads to an increase in the activation energy required to break the bond, and consequently, an increase in bond strength. This increased covalent strength can alter the dynamics of covalent cleavage, leading to what is known as the kinetic isotope effect (KIE) in certain cases. Under certain conditions, including various quantum mechanical aspects of covalent cleavage, the replacement of a covalent CH bond with a covalent CD bond can result in a significant deuterium KIE. A large deuterium KIE for a drug that is a CYP450 substrate can, in certain cases, lead to an improvement in the drug's pharmacokinetic parameters and potentially result in a difference between deuterated and undeuterated drugs. The covalent CD bond in deutetrabenazine meets several chemical and biological criteria to simultaneously provide a deuterium KIE large enough to slow the O-demethylation of the active metabolite of deutetrabenazine compared to tetrabenazine. It is important to note that the magnitude of this deuterium KIE cannot be predicted in advance, and therefore it could not be known beforehand whether the replacement of the CH covalent bond in tetrabenazine with a CD covalent bond resulted in significant and / or improved biological differences.

[0302] Dutetrabenazine or d6-tetrabenazine is a VMAT2 inhibitor.

[0303] In d6-tetrabenazine, six hydrogen atoms are replaced by deuterium atoms, as shown in the diagram above. There is substantial evidence that d6-tetrabenazine forms a stable covalent bond, and that its trideuteromethyl group (-CD3) is a covalently stable portion, and that this bond has no difference or characteristics compared to a methyl group (-CH3).

[0304] Firstly, the covalent nature of CD binding can be established by spectroscopic methods such as infrared (IR) spectroscopy. The characteristic IR absorption of CD stretching at approximately 2000–2300 cm⁻¹ (Miller and Corcelli, 2009) is often used by researchers as a site-specific and non-perturbative probe for protein studies (Miller and Corcelli, 2009; Zimmermann et al., 2011). d6-tetrabenazine has a different IR absorption at 2060–2250 cm⁻¹ due to CD stretching. These absorption bands are not present in the IR spectrum of the undeuterated tetrabenazine.

[0305] Secondly, d6-tetrabenazine is not a salt form of tetrabenazine. The mass spectrum of deutetrabenazine shows a protonated molecular ion at m / z 324.18[M+1]. This is consistent with the predicted mass number of d6-tetrabenazine as an intact molecule.

[0306] Thirdly, the deuterium atoms in d6-tetrabenazine do not exchange with hydrogen under normal physiological conditions. The pKa of the unconjugated aliphatic CH bond is in the range of 45-50, which means that at equilibrium, the ratio of dissociated species to undissociated species is less than 10-45. By comparison, the CH bond of the methoxy group of tetrabenazine, and by extension, the CD bond of the methoxy group of d6-tetrabenazine, are even less acidic, with pKa values ​​reaching 50. This means that the aqueous solution needs to be increased to a pH above 45 before any deuterium atom in d6-tetrabenazine can potentially begin exchanging with a hydrogen atom.

[0307] Finally, d6-tetrabenazine or deutetrabenazine were administered to humans in clinical trials and subjected to various in vitro incubations with multiple enzymatic processes. Known active metabolites and further downstream metabolites were monitored in in vitro incubation and / or in human plasma by LC / MS / MS. These metabolites were synthesized and confirmed to contain the expected tridueromethyl group (-CD3), confirming that the covalent CD binding in deutetrabenazine is stable and carried over into the downstream metabolites of deutetrabenazine. Deutetrabenazine has a different pharmacokinetic profile compared to d0-tetrabenazine.

[0308] Due to the deuterium kinetic isotope effect (KIE), the substitution of hydrogen (H) with hydrogen (D) in covalent CH bonds in small molecule drugs has the ability to attenuate drug metabolism by requiring more energy for cleavage by enzymes such as cytochrome P450 isozymes (CYP450) (Baillie, 1981). The magnitude of the deuterium KIE varies depending on the nature of the CH bond being broken and whether the cleavage of that bond is the rate-limiting step in the oxidative metabolism of the drug by CYP isozymes.

[0309] By reducing metabolism in this manner, the elimination half-life (t 1 / 2), exposure (AUC [area under the plasma level-time curve]), and peak plasma concentration (Cmax) can be altered compared to the non-deuterated form of the drug (Kushner et al., 1999; Baillie, 1981). Substitution of D to H at specific positions in the drug also has the ability to attenuate the breakdown of deuterium-containing metabolites of the deuterated parent drug. Many deuterium substitutions at important oxidative metabolic sites have no effect; thus, empirical data are needed to determine whether deuteration has any potentially relevant outcomes in vivo. Tetrabenazine contains several CH covalent bonds that undergo oxidative metabolism by CYP450 enzymes. For all of the reasons mentioned above, drugs with longer half-lives may offer the potential for higher efficacy, better safety and tolerability, improved quality of life, and long-term cost savings. Using various deuteration patterns, it is possible to (a) reduce or eliminate undesirable metabolites, (b) increase the half-life of the parent drug, (c) reduce the number of doses required to achieve the desired effect, (d) reduce the dose required to achieve the desired effect, (e) increase the formation of active metabolites if any are formed, (f) reduce the production of harmful metabolites in specific tissues, and / or (g) create more effective and / or safer drugs for polypharmacy, whether or not polypharmacy is intended. Deuteration techniques have demonstrated the ability to slow the metabolism of tetrabenazine and reduce inter-patient variability.

[0310] Abbreviations and definitions To facilitate understanding of this disclosure, some terms and abbreviations used herein are defined as follows:

[0311] All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both the incorporated publications or references and those expressly stated or defined herein, the definitions or meanings expressly stated herein shall control all respects.

[0312] The singular forms "a," "an," and "the" may refer to multiple items unless otherwise specified.

[0313] When a range of values ​​is disclosed and the notation "from n1 to n2" or "n1~n2" (where n1 and n2 are numbers) is used, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be between the endpoints and integers or consecutive numbers that include them.

[0314] When used in a list of two or more items, the term "and / or" means that any one of the listed items may be used alone or in combination with any one or more of the listed items. For example, the expression "A and / or B" is intended to mean either A or B, or both, i.e., A only, B only, or a combination of A and B. The expression "A, B and / or C" is intended to mean A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B and C.

[0315] As used herein, the term "about" when referring to measurable values ​​such as the amount, dose, time, or temperature of a compound means that it includes variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.

[0316] As used herein, the term "abnormal" refers to activity or characteristics that differ from normal activity or characteristics.

[0317] As used herein, the term "abnormal muscle activity" refers to muscle activity that differs from muscle activity in a healthy subject. Abnormal activity may be reduced or increased compared to normal activity. Increased muscle activity may result in excessive abnormal movement, excessive normal movement, or a combination of both.

[0318] The term “adverse event” (“AE”) means any undesirable medical event in a patient administered a drug, regardless of whether it is causally related to the treatment. Therefore, an adverse event may be any undesirable or unintended physical sign, symptom, or laboratory parameter that occurs or worsens in the course of this study, or a significant worsening of a disease or any comorbidity under study, regardless of whether it is thought to be related to the study drug. A new condition or a worsening of a pre-existing condition is considered an adverse event. A stable chronic condition (such as arthritis) that existed before study enrollment and does not worsen during this study is not considered an adverse event. A mild AE is one that does not limit the subject’s activity; a moderate AE causes some limitation of normal activity; and a severe AE prevents the subject from performing normal activity.

[0319] A "treatment-related adverse event" is an adverse event that, in the judgment of a physician or clinician, is associated with the administered drug. It should be understood that such a determination is often not simplified to a yes / no question and may rely on a continuity of factors that more or less indicate the AE is treatment-related, such as the proximity of the event's occurrence to the medication, the disappearance of the AE upon discontinuation or reduction of the drug dose, and the failure of other factors that explain the AE (e.g., pre-existing conditions, environmental factors, etc.).

[0320] The term "CYP2D6 inhibitor" refers to a drug that inhibits CYP2D6, and therefore makes it unavailable for the metabolism of other substrate compounds; co-administration of drugs metabolized by CYP2D6 and CYP2D6 inhibitors should be done with caution and frequently at reduced doses due to the high plasma concentrations of the inhibitors. Examples of CYP2D6 inhibitors include amiodarone, celecoxib, chloroquine, chlorpromazine, cimetidine, citalopram, clomipramine, codeine, diavirdin, desipramine, dextropropoxifen, diltiazem, doxorubicin, entacapone (high dose), fluoxetine, fluphenazine, fluvaxamine, haloperidol, labetalol, loberine, lomustine, methadone, mibefladil, moclobemide, nortuloxerin, paroxetine, perphenazine, propafenone, quinacrine, quinidine, ranitidine, risperidone, ritonavir, serindol, sertraline, thioridazine, valproic acid, venlafaxine, vinblastine, vincristine, vinorelbine, and yohimbine. Potent CYP2D6 inhibitors include fluoxetine, alloxetine, bupropion, quinidine, cinacalcet, and ritonavir.

[0321] As used herein in reference to the control of abnormal muscle activity or abnormal involuntary movements (e.g., chorea), the term “degree” is synonymous with “level.”

[0322] As used herein, the term “disorder” refers to an abnormal condition of a part of the body or its normal function that is impaired, and is generally synonymous with and intended to be used interchangeably with the terms “disease,” “syndrome,” and “condition” (in the case of a medical condition), in that they typically manifest by distinguishing between signs and symptoms.

[0323] The terms “to treat,” “to treat,” and “treatment” mean to reduce or neutralize one or more symptoms of a disorder or a disorder associated with a disorder, or to reduce or eliminate the cause of the disorder itself. As used herein, references to “treatment” of a disorder are intended to include prevention.

[0324] The terms “prevent,” “prevention,” and “prevention” refer to methods of delaying or making impossible the onset of a disability and / or its associated symptoms, preventing an object from acquiring a disability, or reducing the risk to an object acquiring a disability.

[0325] The terms "tolerable" and "tolerable" refer to the amount of deuterium-substituted tetrabenazine (e.g., deutetrabenazine) or other drug (e.g., deuterium-substituted VMAT inhibitor or valbenazine) that causes a low rate of adverse events in patients, such as drowsiness, irritability, fatigue, vomiting, and nausea, where the adverse event does not result in dose reduction, discontinuation, or withdrawal of deuterium-substituted tetrabenazine or the other drug. Deuterium-substituted tetrabenazine is also considered tolerable if it does not exacerbate any underlying symptoms such as depression, anxiety, suicidal ideation, or parkinsonism in patients with diseases or conditions such as Huntington's disease, tardive dyskinesia, or Tourette syndrome. Tolerability is the amount of dutetrabenazine (or other drugs, if applicable) that does not require downward adjustment in regular (e.g., daily) doses, or, for example, dose discontinuation due to adverse effects. Tolerable doses may vary between subjects and within subjects over the course of the disease or treatment.

[0326] As used herein in reference to the control of abnormal muscle activity or abnormal involuntary movement (e.g., chorea) in a subject, the term “adequate” refers to an observable and satisfactory level of control for the subject. The clinician or principal investigator in consultation with the subject will determine when an adequate level of control of abnormal muscle activity or abnormal involuntary movement (e.g., chorea) has been achieved. Typically, the sufficiency of the level of control of abnormal muscle activity or abnormal involuntary movement provided by a given amount of drug is influenced by the tolerability of that amount and is often the maximum tolerable dose (“optimal” dose) that results in an observable increase in control. The dose of dutetrabenazine may be increased on a weekly basis until chorea is adequately controlled, until the subject experiences a protocol defined as a “clinically meaningful” adverse event (relevant to the investigational drug and defined as being a) of moderate or severe intensity, or b) meeting the criteria for a serious adverse event (SAE) (or a maximum tolerable dose), or until the maximum tolerable dose is reached. The adequate level may vary between subjects and within subjects over the course of the disease or treatment.

[0327] The terms “improve,” “improve by,” “decrease,” and “decrease by,” used to refer to the level, degree, or amount to which some quality is reduced or improved in a subject or group of subjects as a result of treatment with a compound, mean that the comparison is with an untreated subject or group of subjects. Alternatively, where explicitly stated, these terms may also mean a comparison with a subject or group of subjects treated with standard treatment. Such evaluation criteria may be constructed by reference to relevant scales or assessments known in the industry (see, for example, the disability control and / or disability elimination evaluation scales, and the examples of Likert scales provided herein).

[0328] As used herein, the term "abnormal involuntary movement" includes involuntary movements associated with or caused by a movement disorder.

[0329] The term "subject" refers to animals such as primates (e.g., humans, monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, etc.), lagomorphs, pigs (e.g., pigs, miniature pigs), horses, dogs, and cats, though not limited to these. The terms "subject" and "patient" are used interchangeably in this specification to refer to mammalian subjects such as human patients.

[0330] The GTS-QOL consists of two parts. The first part is typically a 27-question assessment of various aspects of how tics affect the subject's life, each rated on a five-option scale: no problem, minor problem, moderate problem, significant problem, or major problem. One may look at subscales that combine some of these aspects, such as the Physical / Activities of Daily Living (ADL) subscale. The second part is a simple rating of the subject's life satisfaction, with 100 being very satisfied and 0 being very dissatisfied.

[0331] SF-36 Physical Function Score. The SF-36 is a 36-item short-answer health survey used to assess health-related quality of life (Ware, 1996). The SF-36 has been useful in comparing specific populations and the relative burden of various diseases. The SF-36 has been assessed in HD patients and has demonstrated strong construct validity and test-retest reliability, and has also been distinguishable from age-matched controls and reference data on a 10-item Physical Function Scale (Ho, 2004). The entire SF-36 was administered in this study, but the Physical Function Scale (also known as PF-10) was analyzed as an important secondary outcome measure. The Physical Function Scale is a subset of the 10 items of the SF-36 that examines subjects' known health-related limitations in physical activity. The SF-36 Physical Function Score is a 10-item scale that rates a subject's ability to perform everyday physical activities such as walking, climbing stairs, bathing, or dressing. Given that chorea can impair basic motor skills, gait, and walking, it is not expected that individuals with more severely impaired function will experience greater benefits on this assessment criterion.

[0332] The General Impression of Tourette Syndrome Severity (TS-PGIS) is a novel 5-point scale, where 1 indicates no tics, 2 indicates mild tics (not distressing, inconspicuous, or not interfering with daily life), 3 indicates moderate tics (distressing, noticeable, and sometimes interfering with daily life), 4 indicates prominent tics (very distressing, noticeable, and interfering with daily life), and 5 indicates severe tics (severely distressing, always noticeable, and interfering with many daily activities).

[0333] The Tic-Free Interval is a 5-point scale, where 1 indicates at least 1 day since the last tick, 2 indicates an interval of 6 hours to less than 1 day since the last tick, 3 indicates an interval of 1 hour to less than 6 hours since the last tick, 4 indicates an interval of 5 minutes to less than 1 hour since the last tick, and 5 indicates an interval of less than 5 minutes since the last tick.

[0334] The TS-CGI is a 7-point scale scored by clinicians, where 1 indicates normal or no tics, 2 indicates tics may or may not be present, 3 indicates mild, observable motor and / or vocal tics that may or may not be noticed, do not draw attention to the individual, and are not associated with distress or impairment, 4 indicates moderate, observable motor and / or vocal tics that are always noticed, draw attention to the individual, and may be associated with some distress or impairment, 5 indicates prominent, hypermotor and / or vocal tics that are disruptive, always draw attention to the individual, and are always associated with significant distress or impairment, 6 indicates severe, extremely hypermotor and / or vocal tics that are disruptive, always draw attention to the individual, and are associated with injury or inability to perform daily functions, and 7 indicates extreme tics that significantly impair normal daily living.

[0335] The YGTSS is a comprehensive assessment of the various forms and severity of motor and vocal tics. In one embodiment, each of the five categories (number, frequency, intensity, complexity, and interference) is scored from 0 to 5 for both motor and vocal tics, resulting in tic severity scores of 0 to 25 for both the Vocal Tic Severity Score (VTSS) and the Motor Tic Severity Score (MTSS). Taken together, these constitute the Total Tic Severity (TTS) score. Separately, the impairment of a patient's life is scored on a scale of 0 to 50, where 0 indicates no impairment, 10 is minimal, 20 is mild, 30 is moderate, 40 is significant, and 50 is severe, resulting in an impairment score. When the impairment score is added to the TTS score, this constitutes the complete YGTSS Global Severity Score (GSS).

[0336] The Tourette Syndrome Patients' Overall Impression of Change (TS-PGIC) is a 7-point scale, where -3 indicates a very significant deterioration, -2 indicates a significant deterioration, -1 indicates a minimal deterioration, 0 indicates no change, 1 indicates a minimal improvement, 2 indicates a significant improvement, and 3 indicates a very significant improvement.

[0337] The GTS-QOL consists of two parts. The first part is a 27-question assessment of various aspects of how tics affect the subject's life, each rated on a five-option scale: no problem, minor problem, moderate problem, significant problem, or major problem. The second part is a simple assessment of the subject's life satisfaction, with 100 being very satisfied and 0 being very dissatisfied.

[0338] Tick-free interval is a 5-point scale, where 1 indicates at least 1 day since the last tick, 2 indicates 6 hours to less than 1 day since the last tick, 3 indicates 1 hour to less than 6 hours since the last tick, 4 indicates 5 minutes to less than 1 hour since the last tick, and 5 indicates less than 5 minutes since the last tick.

[0339] The term "VMAT2" refers to vesicular monoamine transporter 2, an intrinsic membrane protein that acts to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from the cytosol to synaptic vesicles.

[0340] The term "VMAT2-mediated disorder" refers to a disorder characterized by abnormal VMAT2 activity. VMAT2-mediated disorders can be fully or partially mediated by the modulation of VMAT2. In particular, VMAT2-mediated disorders are those in which inhibition of VMAT2 has some effect on the underlying disorder; for example, administration of a VMAT2 inhibitor results in some improvement in at least some of the patients being treated.

[0341] The terms “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibit VMAT2” refer to the ability of the compounds disclosed herein to alter the function of VMAT2. VMAT2 inhibitors can block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2, or by forming a non-covalent complex. Such inhibition may occur only in specific cell types or be associated with specific biological events. The terms “VMAT2 inhibitor,” “inhibit VMAT2,” or “inhibit VMAT2” also refer to altering the function of VMAT2 by reducing the probability of complex formation between VMAT2 and its native substrate.

[0342] The compounds disclosed herein may exist as therapeutically acceptable salts. As used herein, the term “therapeutically acceptable salt” refers to a therapeutically acceptable salt or amphoteric form of the compound disclosed herein, as defined herein. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable compound with a suitable acid or base. Examples of therapeutically acceptable salts include acid and base addition salts.

[0343] 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, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L- Examples include glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0344] Suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, such as L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, and Examples of organic bases include sopropylamine, N-methyl-glucamine, hydravamin, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0345] The compounds of the inventions in question may be administered as raw chemical substances, but they may also be provided as pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic components together with one or more of the specific compounds disclosed herein, or one or more of their pharmaceutically acceptable salts, prodrugs, or solvates, are provided herein. The appropriate formulation depends on the selected route of administration. Any of the well-known techniques, carriers, and excipients may be used as preferred and as understood in the industry; for example, as described in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the industry, for example, by conventional mixing, dissolution, granulation, sugar-coating, powdering, emulsification, encapsulation, capture, or compression processes. The pharmaceutical compositions may also be formulated as modified-release dosage forms, including delayed, long-acting, extended, sustained, pulsed, controlled, accelerated, and rapid, 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.

[0346] The compositions include those suitable for oral, parenteral (subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary, etc.), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and intraocular) administration, but the most preferred route may depend, for example, on the recipient's condition and impairment. For convenience, the compositions can be provided as unit dosage forms and can be prepared by any method well known in the pharmaceutical industry. Typically, these methods involve the step of binding the compound of the invention in question or its pharmaceutically active salt, prodrug, or solvate ("active ingredient") to a carrier constituting one or more auxiliary components. Generally, the composition is prepared by uniformly and closely binding the active ingredient to a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0347] Formulations of the compounds disclosed herein, suitable for oral administration, can be provided as individual units such as capsules, cachetes, or tablets containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. The active ingredient can also be provided as a bolus, lick, or paste.

[0348] Pharmaceutical preparations for oral administration include tablets, gelatin-based press-fit capsules, and flexible, airtight capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more auxiliary components. Compressed tablets may be prepared by compressing an active ingredient in a free-flowing form, such as a powder or granules, which may be mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent, in a suitable machine. Tablets may be coated or scored to provide a slow or controlled release of the active ingredient therein. All preparations for oral administration should be in a dosage form suitable for such administration. Press-fit capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added. Sugar-coated tablet cores are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of active compound dosages.

[0349] Compounds can be formulated for parenteral administration by injection, such as bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage forms, such as ampoules or multi-dose containers, with the addition of preservatives. Compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulations such as suspending agents, stabilizers and / or dispersants. Formulations may be provided in unit or multi-dose containers, such as sealed ampoules and vials, and can be stored in powder form or freeze-dried state requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile heat-free water, immediately before use. Immediate injection solutions and suspensions can be prepared from the types of sterile powders, granules and tablets previously described.

[0350] Preparations for parenteral administration include aqueous and non-aqueous (oil-based) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The aqueous injection suspension may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0351] In addition to the formulations previously described, the compound can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymer or hydrophobic substance (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

[0352] For administration by cheek or sublingually, the composition may take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions may contain the active ingredient in a sucrose and a fragrance base such as acacia or tragacanth.

[0353] Furthermore, the compound can be formulated in rectal compositions such as suppositories or retained enemas containing conventional suppository bases, such as cocoa butter, polyethylene glycol, or other glycerides.

[0354] Certain compounds disclosed herein can be administered topically, i.e., non-systemically. This includes external application of the compounds disclosed herein to the epidermis or oral cavity, as well as dropping such compounds into the ears, eyes, and nose, such that the compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0355] Suitable formulations for topical administration include liquid or semi-liquid preparations suitable for penetration from the skin to the site of inflammation, such as gels, patches, lotions, creams, ointments, or pastes, and droppers suitable for administration to the eyes, ears, or nose.

[0356] For administration by inhalation, the compound can be delivered by an insuffler, nebulizer, pressure pack, or other conventional means of delivery such as an aerosol spray. The pressure pack may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve for delivering a fixed amount. Alternatively, for administration by inhalation or air delivery, the compound according to the present invention may take the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition can be provided in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, which allow the powder to be administered with the assistance of an inhaler or insuffler.

[0357] A preferred unit-dose formulation contains an effective dose of the active ingredient, or a suitable fraction thereof, as described below herein.

[0358] The compound can be administered orally or by injection at doses of 0.1 to 500 mg / kg / day. The dose range for adult humans is generally 5 mg to 2 g / day. Tablets or other forms of offerings provided in individual units may conveniently contain a certain amount of one or more compounds that are effective in such doses or as units containing multiple doses, for example, 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0359] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration.

[0360] In certain embodiments, the compounds disclosed herein may be formulated or administered using any of the formulations and methods disclosed in U.S. Patent Application No. 14 / 030,322, filed on September 18, 2013, which is incorporated herein by reference in its entirety.

[0361] Compounds can be administered in various ways, for example, orally, topically, or by injection. The precise amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level for any particular patient depends on various factors such as the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, elimination rate, drug combination, the exact disorder being treated, and the severity of the disorder being treated. The route of administration may also vary depending on the disorder and its severity.

[0362] If the patient's condition does not improve at the physician's discretion, the compound may be administered chronically, that is, for a long period of time, such as throughout the patient's lifetime, to improve, or otherwise control or limit the symptoms of the patient's disability.

[0363] If the patient's condition improves at the physician's discretion, the administration of the compound may be carried out continuously or temporarily (i.e., with "drug-free days") over a certain period of time.

[0364] Once the patient's condition improves, a maintenance dose should be administered as needed. Subsequently, the dose, frequency, or both can be reduced as a function of symptoms to a level at which the improved disability is maintained. However, patients may require long-term, intermittent treatment when symptoms recur.

[0365] A method for treating VMAT2-mediated disorders is disclosed herein, comprising the step of administering a therapeutically effective amount of one of the compounds disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof to a subject having or suspected to have such a disorder.

[0366] VMAT2-mediated disorders include, but are not limited to, chronic hypermobility disorder, Huntington's disease, hemisvalris, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and / or any disorders that can be reduced, mitigated, or prevented by the administration of VMAT2 inhibitors.

[0367] Also disclosed herein are methods for treating abnormal muscle activity, abnormal involuntary movements, or motor disorders, comprising the step of administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof to a subject having or suspected to have such a disorder.

[0368] Motor disorders include sitting inability, akinesia, ataxia, athetosis, ballism, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesia (e.g., paroxysmal), blepharospasm, writer's cramp (hand dystonia), laryngeal dystonia (spasmodic dysphonia), and dystonia (generalized, segmental, or localized), essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's disease, and multiple system atrophy (Scheid's disease). Examples include Reger syndrome, myoclonus, Parkinson's disease, levodopa-induced dyskinesia in Parkinson's disease, parkinsonism, progressive supranuclear palsy, restless legs syndrome, Rett syndrome, spasmodic torticollis (cervical dystonia), seizures due to stroke, cerebral palsy, multiple sclerosis, spinal cord or brain injury, stereotypic movement disorder, stereotypic syndrome, Sydenham chorea, synkinesis, tardive dyskinesia, tics, Tourette syndrome, and Wilson's disease.

[0369] In certain embodiments, methods for treating abnormal muscle activity, abnormal involuntary movement, or motor impairment include: (1) reducing inter-individual variability in plasma levels of a compound or its metabolites; (2) increasing the mean plasma level of a compound per dose unit or decreasing the mean plasma level of at least one metabolite of a compound; and (3) increasing the level of at least one cytochrome P in the subject. 450 (4) Inhibition of monoamine oxidase isoforms and / or reduction of metabolism thereof; (5) At least one polymorphically expressed cytochrome P in the subject 450 The process includes administering to a subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof to result in: (5) a decrease in metabolism due to the isoform; (6) a statistically significant improvement in at least one disability control and / or disability elimination endpoint; (7) an improvement in the clinical effect during treatment of the disability; (8) prevention of recurrence, reduction, or delay of the onset of any abnormal nutritional or hepatic parameter as a primary clinical benefit; or (9) a reduction or elimination of any adverse change in any diagnostic hepatic biliary function endpoint compared to a corresponding non-isotope enriched compound.

[0370] In certain embodiments, the inter-individual variability of plasma levels of the compounds disclosed herein or their metabolites is reduced by more than about 5%, more than about 10%, more than about 20%, more than about 30%, more than about 40%, or more than about 50% compared to the corresponding non-isotope-enriched compounds; the mean plasma levels of the compounds disclosed herein are increased; the mean plasma levels of metabolites of the compounds disclosed herein are decreased; and cytochrome P is reduced by the compounds disclosed herein. 450 Alternatively, inhibition of monoamine oxidase isoforms is reduced; or at least one polymorphically expressed cytochrome P 450 The metabolism of the compounds disclosed herein is reduced by the isoform.

[0371] Plasma levels of the compounds disclosed herein or their metabolites can be measured using the methods described in Li et al., Rapid Communications in Mass Spectrometry 2005, 19, pp. 1943-1950; Jindal et al., Journal of Chromatography, Biomedical Applications 1989, 493(2), pp. 392-397; Schwartz et al., Biochemical Pharmacology 1966, 15(5), pp. 645-655; Mehvar et al., Drug Metabolism and Disposition 1987, 15(2), pp. 250-255; Roberts et al., Journal of Chromatography, Biomedical Applications 1981, 226(1), pp. 175-1782; and any of the references cited herein, or any modifications thereof.

[0372] Cytochrome P in mammals 450Examples of isoforms, though not limited to them, include CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, and CYP4B. Examples include CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0373] Examples of monoamine oxidase isoforms in mammals include, but are not limited to, MAO A , and MAO B These are some examples.

[0374] Cytochrome P 450 Isoform inhibition is measured by the method described by Ko et al. (British Journal of Clinical Pharmacology, 2000, 49, pp. 343-351). MAO A Isoform inhibition is measured by the method of Weyler et al. (J. Biol Chem. 1985, 260, pp. 13199-13207). MAO B Isoform inhibition is measured by the method described by Uebelhack et al. (Pharmacopsychiatry, 1998, 31, pp. 187-192).

[0375] Polymorphically expressed cytochrome P in mammals 450 Examples of isoforms, though not limited to them, include CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[0376] Liver microsomes, cytochrome P 450 The metabolic activity of the isoforms and monoamine oxidase isoforms is measured by the method described herein.

[0377] Examples of improvements in disability control and / or disability eradication metrics, or improvements in clinical efficacy, are not limited to the following: b. Improvement in the Unified Huntington's Disease Rating Scale (UHDRS) score; c. Improvement in the total maximum chorea (TMC) score on the UHDRS; d. Improvement in the Total Motor Score (TMC) of the UHDRS; e. Improvement in the patient's overall impression of change (PGIC) score; f. Improvement in the Clinical Global Impression (CGIC) score of the change; g. Improvement in Unified Parkinson's Disease Rating Scale scores, including dysarthria scores; h. Improvement in the Abnormal Involuntary Movement Scale (AIMS) score; i. Improvement in Goetz Dyskinesia Scale scores; j. Improvement in Unified Dyskinesia Rating Scale scores; k. Improvement in PDQ-39 Parkinson's Disease Questionnaire score; l. Improvement in the global primate dyskinesia scale score; m. Improvement in Berg Balance Test scores; n. Improvement in the SF-36 score as a measure of physical function; o. A decrease in the Hospital Anxiety and Depression Scale (HADS) score; p. Decrease in Columbia Suicide Severity Rating Scale (C-SSRS) score; q. Improvement of the Swallowing Disorder Questionnaire (SDQ) score; r. Improvement (decrease) in the Barnes Akathisia Rating Scale (BARS) score; s. A decrease in the Epworth Sleeping Scale (ESS) score; t. Improvement in the modified head and neck dystonia 24 (CDQ-24) score; u. Montreal Cognitive Assessment (MoCA); v. Improvement in Yale Global Tic Severity Scale (YGTSS) scores, including motor tic severity, vocal cord tic severity, overall tic severity score (TTS) impairment, and general tic severity (GSS) score; w. Improvement (decrease) in the Overall Tic Severity Score (TTS); x. Improvement in the Clinical Global Impression (TS-CGI) score for Tourette's syndrome; y. Improvement in the overall impression score of Tourette syndrome (TS-PGIS) in patients with Tourette syndrome; z. Children's Depression Inventory 2 (CDI-2; Parent and Self-Reported Version); aa. The Childhood Columbia Suicide Severity Rating Scale (C-SSRS); bb. Pediatric Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score; cc. Gil de la Tourette syndrome - Quality of Life (GTS-QOL), including the Physical / Activity subscale score of the Daily Living subscale, the Overall Life Satisfaction score measured by the Visual Analog Scale (VAS), the Psychological subscale score, the Obsessive-Compulsive Behavior subscale score, and / or its Cognitive subscale score. These are some examples.

[0378] Examples of diagnostic hepatic biliary function assessment items include, but are not limited to, alanine aminotransferase ("ALT"), serum glutamate-pyruvate transaminase ("SGPT"), aspartate aminotransferase ("AST" or "SGOT"), ALT / AST ratio, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "γ-GTP", or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, hepatic ultrasonography, hepatic nuclear scan, 5'-nucleotidase, and blood proteins. Hepatic biliary assessment items are compared to described normal levels, as described in the Diagnostic and Laboratory Test Reference, 4th edition, Mosby, 1999.

[0379] In addition to their usefulness for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of pets, exotic animals, and livestock, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0380] Combination therapy The compounds disclosed herein may be used in combination with other agents useful in treating VMAT2-mediated disorders. Alternatively, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., an adjuvant alone may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

[0381] Other drugs, adjuvants, or other substances may be administered concurrently with or in sequence with the compounds disclosed herein, via the routes and in the amounts commonly used for them. When the compounds disclosed herein are used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds disclosed herein may be used, but is not required.

[0382] In certain embodiments, the compounds disclosed herein can be combined with one or more dopamine precursors, such as levodopa, but are not limited to these.

[0383] In certain embodiments, the compounds disclosed herein can be combined with one or more DOPA decarboxylase inhibitors, such as carbidopa, but are not limited to these.

[0384] In certain embodiments, the compounds disclosed herein may be combined with one or more catechol-O-methyltransferase (COMT) inhibitors, such as entacapone and tolcapone, but are not limited to these.

[0385] In certain embodiments, the compounds disclosed herein can be combined with one or more dopamine receptor agonists, including, but not limited to, apomorphine, bromocriptine, ropinirole, and pramipexole.

[0386] In certain embodiments, the compounds disclosed herein can be combined with one or more neuroprotective agents, such as selegerin and riluzole, but are not limited to these.

[0387] In certain embodiments, the compounds disclosed herein may be combined with one or more NMDA antagonists, such as amantidine, but are not limited to these.

[0388] In certain embodiments, the compounds disclosed herein include, but are not limited to, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, siamemazine, chlorproetazine, dixylazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, periciazine, thioridazine, mesolidazine, pipothiazine, haloperidol, trifluperidol, merperone, moperone, pipamperone, bromperidol, bemperidol, droperidol, It can be combined with one or more antipsychotic agents such as fluanisone, oxypertine, morindone, certindol, ziprasidone, flupentixol, clopentixol, chlorprothixen, thiothixen, zuclopentixol, fluspirene, pimozide, penfluridol, roxapine, clozapine, olanzapine, ketiapine, tetrabenazine, sulpiride, sultopride, tiapride, remoxiprid, amisulpride, veraliprid, levosulpiride, lithium, protipendyl, risperidone, clotiapine, mosapramine, zotepine, pripiprazole, and paliperidone.

[0389] In certain embodiments, the compounds disclosed herein may be combined with one or more benzodiazepines ("minor tranquilizers"), including, but not limited to, alprazolam, azinazolam, bromazepam, camazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate, estizolam, fludiazepam, flunitrazepam, harazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, and chlordiazepoxide.

[0390] In certain embodiments, the compounds disclosed herein can be combined with olanzapine or pimozide.

[0391] The compounds disclosed herein, but are not limited to, antiretroviral agents; CYP3A inhibitors; CYP3A inducers; protease inhibitors; adrenergic agonists; anticholinergic agents; mast cell stabilizers; xanthines; leukotriene antagonists; glucocorticoid therapeutics; local or general anesthetics; nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., naproxen; antibacterial agents, e.g., amoxicillin; cholesteryl ester transport protein (CETP) inhibitors, e.g., anacetrapib; antifungal agents, e.g., isoconazole; Sepsis treatment agents, e.g., drolecogin-α; steroids, e.g., hydrocortisone; local or general anesthetics, e.g., ketamine; norepinephrine reuptake inhibitors (NRIs), e.g., atomoxetine; dopamine reuptake inhibitors (DARIs), e.g., methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., milnacipran; sedatives, e.g., diazefams; norepinephrine-dopamine reuptake inhibitors (NDRIs), e.g., bupropion; serotonin-norepinephrine-dopamine reuptake inhibitors Pamine reuptake inhibitors (SNDRIs), e.g., venlafaxine; monoamine oxidase inhibitors, e.g., selegiline; hypothalamic phospholipids; endothelin-converting enzyme (ECE) inhibitors, e.g., phosphoramidon; opioids, e.g., tramadol; thromboxane receptor antagonists, e.g., ifetroban; potassium channel openers; thrombin inhibitors, e.g., hirudin; hypothalamic phospholipids; growth factor inhibitors, e.g., PDGF activity modulators; platelet-activating factor (PAF) antagonists; antiplatelet agents For example, GPIIb / IIIa blockers (e.g., abdoximab, eptifibatide, and tyrofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, for example, warfarin; low molecular weight heparin, for example, enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), for example, omapatril rat and gemopatril rat;HMG CoA reductase inhibitors, e.g., pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisvastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or bisastatin); squalene synthase inhibitors; fibrates; bile acid inhibitors, e.g., kestrane; niacin; anti-atherosclerotic agents, e.g., ACAT inhibitors MTP inhibitors; calcium channel blockers, e.g., amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, e.g., carvedilol and metoprolol; antiarrhythmic agents; diuretics, e.g., chlorothiazide, hydroxylothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trixylomethiazide, polythiazide, benzothiazide, ethacrylic acid, trixylomethiazide Linafen, chlorsalidon, furosenild, musolimin, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, e.g., tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); antidiabetic agents, e.g., biguanides (e.g., metformin), glucosidase inhibitors (e.g., Acarbose), insulin, meglitinide (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glybrid, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, e.g., spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, e.g., PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory agents; antiproliferative agents, e.g., methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;Anticancer agents and cytotoxic agents (e.g., alkylating agents, e.g., nitrogen mustard, alkyl sulfonates, nitrosourea, ethyleneimine, and triazenes); antimetabolites, e.g., leaf; Acid antagonists, purine analogs, and pyridine analogs; antibiotics, e.g., anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes, e.g., L-asparaginase; farnesyl-protein transferase inhibitors; hormones, e.g., glucocorticoids (e.g., cortisone), estrogens / anti-estrogens, androgens / anti-androgens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule disruptors, e.g., ectinacidin; microtubule stabilizers, e.g., paclitaxel, docetaxel, and epothyron AF; plant-derived products, e.g., vinca alkaloids, epipodophyllotoxin, and taxanes; and Topoisomerase inhibitors; prenyl protein transferase inhibitors; and cyclosporine; steroids, e.g., prednisone and dexamethasone; cytotoxic agents, e.g., azatipurine and cyclophosphamide; TNF-alpha inhibitors, e.g., tenidap; anti-TNF antibodies or soluble TNF receptors, e.g., etanercept, rapamycin, and leflunide; and cyclooxygenase-2 (COX-2) inhibitors, e.g., celecoxib and rofecoxib; and combinations, e.g., hydroxyureas, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, e.g., other classes of compounds such as cisplatin, satraplatin, and carboplatin, which may also be administered in combination.

[0392] Thus, in another embodiment, a particular embodiment provides a method for treating such a disorder in a subject requiring treatment for a VMAT2-mediated disorder, comprising the step of administering to the subject a certain amount of a compound disclosed herein that is effective in mitigating or preventing the disorder in the subject, together with at least one further agent for treating the disorder. In a related embodiment, a particular embodiment provides a therapeutic composition comprising at least one compound disclosed herein together with one or more further agents for treating a VMAT2-mediated disorder.

[0393] General synthesis methods for preparing compounds Compounds disclosed herein may be obtained by methods known to those skilled in the art and their routine modifications, and / or by U.S. Patent Application Publication No. 20100130480 (paragraphs

[0093] -

[0121] ), U.S. Patent Application Publication No. 20120003330 (paragraphs

[0104] -

[0162] ), WO 2005077946; WO 2008 / 058261; EP 1716145; Lee et al., J. Med. Chem., 1996, (39), pp. 191-196; Kilbourn et al., Chirality, 1997, (9), pp. 59-62; Boldt et al., Synth. Commun., 2009, (39), pp. 3574-3585; Rishel et al., J. Org. It can be prepared in accordance with procedures similar to those described in Chem., 2009, (74), pp. 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993, 44(4), pp. 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), pp. 871-873; Ivanov et al., Heterocycles 2001, 55(8), pp. 1569-1572; U.S. Patent No. 2,830,993; U.S. Patent No. 3,045,021; WO 2007130365; WO 2008058261 (these are incorporated herein by reference in their entirety), and the references cited herein, and their everyday modifications.

[0394] Isotope hydrogen can be introduced into the compounds disclosed herein by synthetic techniques using deuterated reagents with a predetermined integration rate; and / or by exchange techniques where the integration rate is determined by equilibrium conditions and can vary significantly depending on reaction conditions. Synthetic techniques in which tritium or deuterium is directly and specifically inserted by tritized or deuterated reagents with known isotopic content can result in high tritium or deuterium abundances, but may be limited by the required chemicals. On the other hand, exchange techniques can result in lower tritium or deuterium integration, and the isotopes are often distributed across many sites on the molecule.

[0395] In certain embodiments, examples of compounds of the present invention include compounds selected from the list set forth in paragraph

[0122] of U.S. Patent Application Publication No. 20100130480 and paragraph

[0163] of U.S. Patent Application Publication No. 20120003330 (incorporated herein by reference).

[0396] Changes in the in vitro metabolic properties of certain compounds disclosed herein compared to non-isotope enriched analogs, and methods for determining such changes, are described in paragraphs

[0125] of U.S. Patent Application Publication 20100130480 and paragraphs

[0165] -

[0185] of U.S. Patent Application Publication 20120003330 (incorporated herein by reference).

[0397] formulation The compounds can be formulated for use in the drug regimens and methods disclosed herein by methods known in the art, such as those disclosed in U.S. Patent Application Publication No. 2014 / 0336386. Examples of these formulations are provided below.

[0398] Table 1 below discloses the components of a 350 mg total weight gastric erosive granular tablet formulation containing 15 mg of (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinoridine-2-one.

[0399] [Table 1]

[0400] d6-tetrabenazine (ground) is mixed with mannitol powder, microcrystalline cellulose, PVP K29 / 32 and Tween 80 (polysorbate 80) in a high-shear granulator and first dried-mixed at a high thrust and cutting speed for 5 minutes. Purified water is added to the mixed powder while mixing at a high thrust and cutting speed to granulate the material. Further mixing and water addition at a high thrust and cutting speed is continued until the desired granulation endpoint is achieved. The resulting granules are wet-sieved to break up any oversized clumps, and the material is added to a fluidized bed dryer and dried at 60°C until the desired LOD (loss on drying) is achieved. The dried material is sieved through a #20 mesh screen to grind any oversized material to a particle size just below 20 mesh. The dried and sized materials are mixed with spray-dried mannitol and POLYOX® N60K in a diffusion mixer (V-Blender) and blended for 15 minutes. Magnesium stearate is then added to the blended material in the V-Blender through a #30 mesh screen. The contents are then lubricated for 3 minutes and discharged for tablet compression. The lubricated blend is compressed into 350 mg theoretical weight tablets using a rotary tablet press equipped with a punch and a die of the desired shape and size.

[0401] 7.5 mg of d6-tetrabenazine gastric erosion long-release (small tablet) (Formulation A). Table 2 below discloses the components of a 350 mg total weight gastric erosion granular formulation tablet containing 7.5 mg of d6-tetrabenazine. The process is the same as that described for Example 1.

[0402] [Table 2]

[0403] 15 mg d6-tetrabenazine gastric retention long-release (large tablet) (Formulation B). The following Table 3 discloses the components of a 700 mg total weight gastric retention formulation tablet containing 15 mg d6-tetrabenazine. The gastric retention tablet is an elongated capsule with dimensions of approximately 0.7087 inches in length and 0.3071 inches in width, with rounded ends on opposite sides having a cup depth of 0.0540 inches.

[0404] [Table 3]

[0405] 7.5 mg d6-tetrabenazine gastric retention long-release (large tablet) (Formulation B). Table 4 below discloses the components of a 700 mg total weight gastric retention formulation tablet containing 7.5 mg d6-tetrabenazine. The gastric retention tablet is an elongated capsule with dimensions of approximately 0.7087 inches in length and 0.3071 inches in width, with rounded ends on opposite sides having a cup depth of 0.0540 inches. The process is the same as described for Example 1, except the theoretical compressed weight is 700 mg.

[0406] [Table 4]

[0407] 6 mg d6-tetrabenazine immediate-release tablets. Table 5 below discloses the components of 125 mg total weight immediate-release tablets containing 6 mg of d6-tetrabenazine.

[0408] [Table 5]

[0409] d6-tetrabenazine (ground) is mixed with mannitol powder, microcrystalline cellulose, sodium glycolate starch, PVP K29 / 32 and Tween 80 (polysorbate 80) in a high-shear granulator and first dried-mixed at a high thrust and cutting rate for 5 minutes. Purified water is added to the mixed powder while mixing at a high thrust and cutting rate to granulate the material. Further mixing and water addition at a high thrust and cutting rate is continued until the desired granulation endpoint is achieved. The resulting granules are wet-sieved to break up any oversized lumps, and the material is added to a fluidized bed dryer and dried at 60°C until the desired LOD (loss on drying) is achieved. The dried material is sieved through a #20 mesh screen to grind any oversized material to a particle size just below 20 mesh. The dried and sized material is mixed with spray-dried mannitol and sodium glycolate starch.

[0410] In all methods and compositions disclosed herein using deutetrabenazine, deutetrabenazine can be administered or formulated as part of the pharmaceutical compositions disclosed in Tables 1 to 5 above.

[0411] Clinical trials and results First-HD First-HD was a randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the efficacy, safety, and tolerability of deutetrabenazine in subjects with chorea associated with hemodialysis (HD). This trial was conducted in the United States and Canada in collaboration with the Huntington Study Group.

[0412] Test design In the First-HD study, participants were treated with either dutetrabenazine or placebo, starting with 6 mg once daily and gradually increasing weekly to a maximum dose of 24 mg twice daily (total maximum daily dose of 48 mg). A total of 90 participants (45 in each group) were enrolled for 13 weeks of evaluation. Participants were individually titrated to the optimal dose for up to 8 weeks, maintained at the optimal dose for 4 weeks, and weaned off the study drug in the final week of the study.

[0413] Subject aptitudes, demographics, and baseline characteristics Of the 90 randomized participants, 87 completed the trial. The study population was typical of individuals with chorea associated with HD. At baseline, the mean age of the participants was 53.7 years. The majority of participants were Caucasian (92.2%) and male (55.6%). The mean CAG repeat length across the participant populations was 43.9. At baseline, the mean TMC score was 12.7 across the entire population (ranging from 8.0 to 19.5).

[0414] Test evaluation items and measured values The primary efficacy endpoint for the trial was the change from baseline to maintenance therapy in the maximum chorea score on the UHDRS (average values ​​at weeks 9 and 12). The total maximum score, or TMC, is a physician-based quantitative assessment of chorea in seven body regions: face, mouth / tongue, torso, and limbs, with higher scores indicating more severe chorea. This is the same endpoint accepted by the FDA in 2008 when tetrabenazine was considered and approved (NDA 21894).

[0415] The Transmuscular Motor Score (TMS) of the UHDRS was pre-designated as an additional efficacy assessment item in First-HD. The TMS assesses all motor characteristics of HD, including items that address non-chorea characteristic motor abnormalities such as dystonia, gait, parkinsonism, and postural instability.

[0416] The clinical relevance of changes in TMC scores was assessed along with four pre-specified secondary endpoints that evaluated changes from baseline to the end of treatment (week 12). These secondary endpoints were tested in a hierarchical manner: 1. Treatment success based on the overall impression of patient change (PGIC); 2. Treatment success based on the clinically comprehensive impression (CGIC) of change; 3. The SF-36 Physical Function Scale; and 4. Equilibrium as assessed by the Berg Balance Test (BBT).

[0417] PGIC and CGIC are single-item questionnaires, respectively, used to assess the overall HD symptoms of subjects at specific visits following initial therapy. Both assessments evaluate the overall response to therapy using a 7-point Likert scale, where responses range from very significant deterioration (-3) to very significant improvement (+3). Patients and physicians were asked, “How would you describe yourself (or the subject) regarding your (or the subject's) overall Huntington’s disease symptoms compared to immediately before starting the study drug?” Treatment success on these scales was defined as a rating of significant or very significant improvement at week 12. Subjects who did not respond at week 12 were considered treatment failures.

[0418] Adverse events (AEs) and their potential association with treatment were also monitored. Categories of specific focus AEs included those known to be associated with tetrabenazine use: Mental disorders: insomnia, depression / agitated depression, abnormal dreams, restlessness, anxiety, suicidal ideation, compulsive-compulsive disorder, impulsive behavior, and sleep disorders; • Nervous system disorders: drowsiness, dizziness, restlessness / inability to sit still, cognitive impairment, salivation, dyskinesia, migraine, headache, loss of consciousness, and fainting (syncope); • Systemic disorders: irritability, fatigue, gait disturbance, chest pain, and depression; and • Gastrointestinal disorders: diarrhea, dry mouth, constipation, nausea, epigastric pain, indigestion, frequent bowel movements, gastrointestinal pain, vomiting, difficulty swallowing, flatulence, and excessive salivation.

[0419] In addition to AE reporting, potential asymptomatic toxicity due to excessive monoamine depletion was monitored using assessment scales. Such safety scales were used in the tetrabenazine development program. These scales applied in First-HD included the Hospitalization Anxiety and Depression Scale (HADS), the Columbia Suicide Severity Rating Scale (C-SSRS), the Swallowing Difficulty Questionnaire (SDQ), the Unified Parkinson's Disease Rating Scale (UPDRS [Dysarthria]), the Barnes Sitting Disorder Rating Scale (BARS), and the Epworth Sleepiness Scale (ESS). Furthermore, the UHDRS, including cognitive, behavioral, and functional assessment criteria, was administered at key visits.

[0420] Since dysphagia is a common problem in patients with Parkinson's disease (HD), the Swallowing Difficulty Questionnaire (SDQ) was used beforehand to assess dysphagia during the study. When this 15-item assessment was validated in patients with Parkinson's disease, it demonstrated a highly sensitive and accurate method for identifying patients with dysphagia arising from different etiologies. The SDQ is recommended by the National Institute of Neurological Disorders and Stroke's Common Data Elements for assessing dysphagia in Parkinson's disease, and thus is relevant to patients with HD, given that they may also experience bradykinesia and other Parkinson's symptoms as part of their condition.

[0421] Slight fluctuations in vital signs (blood pressure, heart rate, respiratory rate, and body temperature) were observed during the study.

[0422] result The mean dose at the end of the 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. The mean dose for the 10 patients in the deutetrabenazine group with impaired CYP2D6 function (those with impaired metabolism or on potent CYP2D6 inhibitors) was 34.8 mg (3.8 mg, range 30–42 mg). Overall compliance rates were 94.1% and 95.1% for the placebo and deutetrabenazine groups, respectively.

[0423] Treatment with deutetrabenazine resulted in improvements in all evaluation parameters and a reduction in the incidence of adverse events. In the following results, DTBZ = deutetrabenazine, CI = confidence interval (based on t-distribution); SD = standard deviation; least squares mean; and p-value were obtained from a two-tailed test of the treatment effect and from analysis of a covariate model using the treatment term and baseline score as a covariate.

[0424] Total maximum chorea score (TMC). Treatment with deutetrabenazine resulted in robust improvement of the maximum chorea score. The TMC score at a given time point is determined from item 12 of the UHDRS. The change in TMC is the difference between baseline and maintenance therapy values. Baseline values ​​are the mean values ​​from screening and day 0, and maintenance therapy values ​​are the mean values ​​from week 9 and week 12. For the primary endpoint, subjects receiving deutetrabenazine achieved a significant 2.5-unit reduction in TMC score from baseline to maintenance therapy compared to placebo (p<0.0001). This reduction in maximum chorea represented a 21-percentage-point decrease compared to placebo (p<0.0001). Deutetrabenazine (DTBZ) was administered at approximately half the daily dose of tetrabenazine. Therefore, the efficacy of deutetrabenazine was achieved at approximately half the daily dose of tetrabenazine.

[0425] [Table 6]

[0426] Total Motor Score (TMS). Furthermore, a statistically significant improvement of 4.0 TMS was observed compared to placebo. The fact that the TMS improvement was larger in magnitude than the TMC score improvement (-2.5 units) suggests that, in addition to the reduction of chorea, deutetrabenazine treatment also benefits other motor symptoms of HD. While the majority of this improvement was attributable to chorea, the total maximum dystonia score also contributed, with a 0.9 (SE 0.24) point improvement for deutetrabenazine compared to a 0.1 (SE 0.32) point improvement for placebo (p=0.02). From baseline to maintenance therapy, TMC improved by 37% in the deutetrabenazine group compared to a 16% improvement in the placebo group (p<0.0001). Changes in other UHDRS motor components did not differ significantly between the treatment groups, including no significant differences in parkinsonism subscores (finger tapping; pronation / supination; rigidity; bradykinesia; gait; tandem gait; and backward thrust pull test score) between the deutetrabenazine group and the placebo group.

[0427] [Table 7]

[0428] Overall Motor Score: Comparison with tetrabenazine. In contrast, in a 12-week placebo-controlled trial, tetrabenazine demonstrated improvement in the UHDRS TMC score, but tetrabenazine treatment did not show a statistically significant improvement in TMS (Huntington Study Group, 2006). These results suggest that tetrabenazine controls chorea associated with HD, but patients may experience a potential decline in motor function that offsets the observed benefit to chorea.

[0429] Conclusion: Therefore, duetetrabenazine can generally be a good choice for the treatment of motor disorders. It is noteworthy that duetetrabenazine achieved efficacy at approximately half the daily dose of tetrabenazine.

[0430] Patient overall impression of change (PGIC) and clinical overall impression of change (CGIC). At the end of therapy, 51% (23 out of 45) of the deutetrabenazine-treated patients were significantly or very significantly improved based on PGIC compared to 20% (9 out of 45) in the placebo group (p=0.0020). Similar findings were observed by the treating physicians, with 42% (19 out of 45) of the deutetrabenazine-treated patients being assessed as having achieved treatment success based on CGIC compared to 13% (6 out of 45) in the placebo group (p=0.0022). These results indicate that the deutetrabenazine-treated patients experienced a clinically meaningful benefit to the overall symptoms of HD, and that the treating clinicians were also able to observe this benefit.

[0431] These improvements in physician and patient assessment scores indicate that the improvements measured by TMC and TMS correspond to improvements in HD symptoms, further supporting the clinical benefits of dutetrabenazine.

[0432] [Table 8]

[0433] SF-36 Physical Function Score. The SF-36 Physical Function Score is a patient-reported measure that has been used in many disease states and was selected as an important secondary outcome measure to assess physical activity relevant to patients living with HD. The 10-item Physical Function Score asks patients about self-care activities such as bathing, dressing, lifting or carrying groceries, climbing one or more stairs, bending, kneeling, walking 100 yards or more, and moderate to vigorous activity. The SF-36 Physical Function Score has been shown to measure the impairments experienced by people living with HD.

[0434] The mean change in the SF-36 physical function score from baseline to week 12 is provided below. Subjects treated with deutetrabenazine showed a mean improvement of 0.74 units from baseline compared to a worsening of 3.61 units in the placebo group (a difference of 4.3 units). In subjects with more severe chorea at baseline (TMC > median of population, or TMC > 12; n=49), the benefit of deutetrabenazine to physical function was more pronounced, showing a mean improvement of 7.1 units compared to placebo (p=0.0075).

[0435] Changes in the SF-36 physical function score from baseline to week 12 showed that subjects treated with SD-809 had greater improvements in physical function compared to subjects treated with placebo (p=0.03). Analysis of SF-36 by baseline severity of chorea showed that SD-809 had a greater benefit in subjects with more severe chorea (p=0.0075). Given that chorea can impair basic motor skills, gait, and walking, it is not surprising that subjects with more deteriorated function would experience a greater benefit with this assessment criterion.

[0436] Considering the significant negative impact of chorea on patients' quality of life and physical function, statistically significant improvements in the subjective assessment of the ability to perform activities of daily living further support the clinical benefits of dutetrabenazine.

[0437] [Table 9]

[0438] The Berg Balance Test (BBT) is a 14-item balance assessment used to evaluate whether chorea relief has an effect on balance, as many medications currently used to treat chorea can worsen balance. The BBT was evaluated as both a safety evaluation criterion and an efficacy evaluation item. As summarized below, deutetrabenazine did not worsen balance at the end of treatment, and in fact, the data numerically favored deutetrabenazine, but the improvement was not statistically significant (p=0.1415). Furthermore, there was no statistically significant difference between deutetrabenazine and placebo in terms of BBT observed during the course of the study.

[0439] [Table 10]

[0440] Adverse Events. Dutetrabenazine was generally well tolerated. The overall proportion of adverse events (AEs) was the same between the dutetrabenazine and placebo groups, with (60.0%) of subjects in each group experiencing at least one AE. There were no deaths in the study. One subject in the dutetrabenazine group had two serious AEs (cholecystitis and agitated depression), and one subject in the placebo group had one serious AE (chronic obstructive pulmonary disease, or COPD relapse). The same subject in the dutetrabenazine group experiencing serious AEs also reported suicidal ideation, which was not considered a serious AE, and subsequently withdrew from the study due to agitation AE. In the placebo group, one subject reported suicidal ideation on the Columbia Suicide Severity Rating Scale, and one subject withdrew from the study due to atrial fibrillation AE. Evidence of good tolerability is further demonstrated by the same proportion of AEs resulting in dose reduction, dose discontinuation, and withdrawal. Finally, CYP2D6 gene status did not affect the rate of drug administration or adverse events (AEs) in this study. As expected, patients with genetic or concomitant drug-induced metabolic deficiencies received slightly less dose and did not exhibit further AEs, which supports the view that deutetrabenazine administration can be clinically managed without relying on expensive genotyping.

[0441] [Table 11]

[0442] Similar rates of adverse events (AEs) were observed among the psychiatric and nervous system tissues, which are particularly important areas for patients with HD. The number of subjects reporting AEs in specific organ-specific categories of psychiatric, nervous system, gastrointestinal, and other systemic disorders is listed in Table 12 below. These tissues are highlighted because they encompass many of the underlying symptoms observed in patients with HD and were also frequent AEs observed with tetrabenazine. Subjects treated with duetetrabenazine had a low rate of insomnia, depression, anxiety, agitation, suicidal ideation, orthostatic hypotension, irritability, and fatigue, and these rates were similar to or lower than the incidence observed in placebo-treated subjects. Importantly, parkinsonism or dysphagia AEs were not reported in the duetetrabenazine group. The most common adverse event observed in the deutetrabenazine group was drowsiness, which occurred in 11.1% of subjects compared to 4.4% in the placebo group, or a drug-placebo difference of 6.7%.

[0443] [Table 12]

[0444] Safety. In addition to reporting adverse events (AEs), potential asymptomatic toxicity due to excessive monoamine depletion was monitored using assessment scales. Such safety scales were used in the tetrabenazine development program. These scales applied in First-HD included the Hospitalization Anxiety and Depression Scale (HADS), the Columbia Suicide Severity Rating Scale (C-SSRS), the Swallowing Difficulty Questionnaire (SDQ), the Unified Parkinson's Disease Rating Scale (UPDRS [Dysarthria]), the Barnes Sitting Disorder Rating Scale (BARS), and the Epworth Sleepiness Scale (ESS). Furthermore, the UHDRS, including cognitive, behavioral, and functional assessment criteria, was administered at key visits.

[0445] These safety measures showed small, clinically insignificant differences between groups, indicating that dutetrabenazine did not cause depression, anxiety, suicidal tendencies, orthostatic intolerance, drowsiness, or speech difficulties. In fact, swallowing function, a significant cause of morbidity and mortality in patients with hemodialysis (HD), was shown to be significantly improved in dutetrabenazine-treated subjects compared to placebo, consistent with improvements observed in motor function. The clinical relevance of this improvement is described below.

[0446] Dysphagia. Since dysphagia is a common problem in patients with HD, the Swallowing Difficulty Questionnaire (SDQ) was used beforehand to assess dysphagia during the study. When this 15-item assessment was validated in patients with Parkinson's disease, it was shown to be a highly sensitive and accurate means of identifying patients with dysphagia resulting from different etiologies. The SDQ is recommended by the National Institute of Neurological Disorders and Stroke's Common Data Elements for assessing dysphagia in Parkinson's disease, and thus is relevant to patients with HD, given that they may also have bradykinesia and other Parkinson's symptoms as part of their disease. Figure 2 shows the mean change from baseline in the SDQ over time, demonstrating a significant improvement in swallowing with deutetrabenazine treatment compared to placebo.

[0447] Further UHDRS assessment. The UHDRS rating scale was assessed throughout the First-HD trial and its safety was monitored. Assessment of the parkinsonism subscore of the UHDRS motor assessment (Part I) did not identify evidence of parkinsonism in subjects treated with deutetrabenazine or placebo, which was 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 questionnaire.

[0448] The results of the UHDRS cognitive assessment (Part II) also did not show any meaningful change from baseline or a consistent trend between treatment groups, which indicates that there was no decline in cognitive function due to the treatment.

[0449] The UHDRS Behavioral Assessment (Part III) showed improvement in the mean overall behavior score in subjects treated with dutetrabenazine compared to the placebo group, although the difference did not achieve statistical significance. Importantly, there was no worsening of depression, apathy, self-esteem, irritability, aggressive behavior, suicidal ideation, hallucinations, or delusions. The overall score improvement was induced by differences in anxiety and obsessive-compulsive behaviors (Figures 4A-4C).

[0450] The UHDRS functional assessment scores (Part IV), independent scale scores (Part V), and overall functional capacity score (Part VI), assessed at baseline and again at week 12, did not show any clinically relevant changes from baseline or differences between treatment groups in any of the treatment groups.

[0451] Slight fluctuations in vital signs (blood pressure, heart rate, respiratory rate, and body temperature) were observed during the study; these changes were similar overall in the deutetrabenazine and placebo groups and were not considered clinically significant. No consistent intergroup differences were observed. Furthermore, there was no evidence that hypotension, dizziness, or orthostatic hypotension was associated with deutetrabenazine treatment.

[0452] Body weight. Compared to the placebo group, the deutetrabenazine treatment resulted in a mean weight gain of approximately 2.1 kg (at week 12, the mean (SD) change in body weight was +1.8 (3.4) kg for deutetrabenazine compared to -0.30 (2.5) kg for placebo (treatment effect, +2.1 kg)). Weight gain correlated with improved treatment outcomes and health in patients with chorea, and in addition to improvements in functional or behavioral symptoms such as anxiety that can suppress appetite, it may also contribute to a reduction in chorea (where improved swallowing can lead to better food intake, which, when combined with the reduced calorie energy used due to the reduction of abnormal involuntary movements, results in weight gain).

[0453] Adverse events and safety: Comparison with tetrabenazine. The fluctuating pharmacokinetics of tetrabenazine affect its tolerability and may limit its clinical use. The circulating active metabolites, α- and β-dihydrotetrabenazine, have short half lives. These short half lives necessitate frequent dosing and lead to large fluctuations in plasma concentrations. The high peak concentration and plasma level variability associated with tetrabenazine may contribute to the often observed low tolerability.

[0454] Therefore, the prescribing information for tetrabenazine contains several warnings regarding potential adverse effects and safety issues: The warning label on the box indicates that tetrabenazine increases the risk of depression and suicidal ideation and behavior (suicidal tendencies) in patients with hemodialysis (HD). Adverse events such as drowsiness / sedation, insomnia, depression, restlessness, anxiety, and fatigue occurred at a higher rate in patients treated with tetrabenazine compared to those treated with placebo (see Table # below). • In 52% (28 out of 54) of patients randomized to tetrabenazine, dose increases were discontinued or the dose of the study drug was reduced due to adverse events. In a 12-week randomized controlled trial of tetrabenazine, adverse events suggestive of parkinsonism (e.g., parkinsonism, bradykinesia, hypertonia, rigidity) were observed in 15% of tetrabenazine patients compared to 0% of placebo patients. • Warnings and precautions for use describe the risk of dysphagia, a known side effect of reduced dopaminergic neurotransmission and an underlying symptom of HD. While a low rate of dysphagia was reported in a 12-week trial, dysphagia was observed in 8%–10% of tetrabenazine-treated patients in an open-label trial, with some cases associated with aspiration pneumonia. Although it is unclear whether these cases were related to the treatment, the FDA expressed concern that events of dysphagia, which can have devastating clinical outcomes, may be significantly underestimated in the tetrabenazine NDA. Notably, in a retrospective study of 98 patients treated with tetrabenazine for hypermotor impairment, dysphagia was observed in 19% of patients. At 50 mg, tetrabenazine caused a mean increase of approximately 8 ms in the QTc interval (90% two-sided confidence interval [CI]: 5.0, 10.4 ms).

[0455] The safety profile of tetrabenazine observed in the 12-week controlled trial will be reflected in the prescribing information as summarized below.

[0456] [Table 13]

[0457] Compared to dutetrabenazine, tetrabenazine is thought to cause more harmful effects.

[0458] ARC-HD In the second clinical trial, a method was implemented to switch patients with well-controlled chorea from tetrabenazine treatment to duetetrabenazine treatment. The Alternative to Alleviate Chorea in Huntington's Disease (ARC-HD) was an open-label, single-arm trial inviting subjects who had received FDA-approved doses of tetrabenazine for chorea treatment or who had successfully completed First-HD.

[0459] Thus, the trial included two cohorts. The rollover cohort (75 participants) successfully completed the First-HD trial described above, including a one-week washout; the switch cohort (37 participants) switched overnight from a stable dosing regimen with tetrabenazine (8 weeks or more) to duetetrabenazine, based on a conversion method designed to achieve equivalent systemic exposure to the sum of α and β metabolites. Other important patient eligibility criteria for the trial included a clear diagnosis of HD as indicated by characteristic motor test features; documentation of an extended cytosine adeninganine (CAG) repeat (≥37) and a total functional capacity (TFC) score of ≥5 at or prior to screening; the ability to walk independently for at least 20 yards (with permitted walkers or assistive devices such as canes); and that participants had a trusted caregiver who interacted with them on a daily basis, supervised the administration of the study drug, ensured attendance at study visits, and, if necessary, participated in assessments. Key exclusion criteria included severe untreated or poorly treated psychosis (e.g., depression) at screening or baseline; concomitant use of dopamine receptor antagonists, dopamine agonists, levodopa, reserpine, N-methyl-D-aspartate receptor antagonists, or monoamine oxidase inhibitors within 30 days of screening or baseline; and a score of 11 or higher on the depression subscale of the Hospitalization Anxiety and Depression Scale (HADS), a score of 11 or higher on the Swallowing Difficulty Questionnaire (SDQ), or a Unified Parkinson's Disease Rating Scale (UPDRS) dysarthria score of 3 or higher at screening or baseline.

[0460] Participants were 58% male, 95% white, and had an average age of 54 years. The mean (SD) TMC score at baseline was 12.2 (4.6), and the mean (SD) CAG repeat length was 44 (3.7).

[0461] Test design Guidelines for investigators regarding the conversion of subjects from stable doses of tetrabenazine to duetetrabenazine in the ARC-HD switch trial were designed to minimize the risk of dose conversion resulting in loss of efficacy or increased adverse events. The conversion methods applied were based on modeling and simulation of Phase 1 pharmacokinetic data for duetetrabenazine and tetrabenazine. The objective of the pharmacokinetic analysis was to identify initial dose regimens of duetetrabenazine that were predicted to provide steady-state exposure to active α and β metabolites with a steady-state AUC lower than or equal to, but with a lower Cmax than, the predicted steady-state AUC of the active α and β metabolites of tetrabenazine.

[0462] In a Phase 1, single-center, open-label, cross-clinical study, 24 healthy volunteers each received a single dose of either 25 mg of tetrabenazine or 15 mg of deutetrabenazine. One of the objectives of this clinical trial was to evaluate and compare the safety of deutetrabenazine with that of tetrabenazine.

[0463] The switch cohort participants completed a full screening assessment. Subsequently, eligible participants for enrollment in the study were converted from their tetrabenazine dose regimen to a duetetrabenazine dose regimen predicted to be equivalent to their current tetrabenazine regimen. Participants received their current tetrabenazine regimen throughout midnight on day 0 and switched to their assigned duetetrabenazine regimen the following morning (day 1 of the study). The initial dose was based on a conversion method defined by a phase 1 pharmacokinetic comparison of duetetrabenazine and tetrabenazine, suggesting an initial dose of duetetrabenazine of approximately 50% of the current tetrabenazine dose (Table 14). After the first week of duetetrabenazine treatment, a dose that adequately controlled chorea was identified, and the dose of duetetrabenazine was adjusted up or down once a week in 6 mg / day increments until the participant experienced a “clinically meaningful” adverse event as defined in the protocol or reached the maximum tolerable dose. The principal investigator, in consultation with the patient and caregiver, determined when a sufficient level of chorea control was achieved. If a patient experienced a clinically significant adverse event attributable to duutetrabenazine, the principal investigator determined whether dose reduction or discontinuation was necessary.

[0464] [Table 14]

[0465] In the rollover cohort, participants completed a one-week washout at the end of First-HD, during which their mean TMC score returned to baseline. The dutetrabenazine dose for these participants was titrated from a starting dose of 6 mg per day to a dose that controlled chorea and was well-tolerated.

[0466] Oral tablets of 6 mg, 9 mg, and 12 mg strength were used for both cohorts. Doses of 12 mg or higher were administered in two divided doses approximately 10 hours apart. All study treatment regimens were administered orally with food. The maximum total daily dose of deutetrabenazine was set at 72 mg per day unless the subject was receiving a potent CYP2D6 inhibitor (e.g., paroxetine), but the maximum total daily dose was 36 mg if the subject was receiving a potent CYP2D6 inhibitor.

[0467] Participants participated in regular clinic visits to assess safety and establish the optimal dose. The principal investigator, in consultation with the participants and caregivers, determined when a sufficient level of chorea control was achieved; the dose of DTBZ could be increased on a weekly basis until chorea was adequately controlled and the participant experienced a clinically significant adverse event defined by the protocol, or until the maximum tolerable dose was reached. During the long-term treatment, all participants had regular contact with the study site for safety and chorea control assessments. The long-term treatment will continue until deutetrabenazine becomes commercially available in the United States.

[0468] A total of 37 subjects with chorea associated with hemoglobin (HD) that were well-controlled with tetrabenazine and who were switched from tetrabenazine to duetetrabenazine in the ARC-HD switch were included in an analysis conducted to evaluate the maintenance of chorea control after dose conversion. Each subject in this analysis was converted from tetrabenazine treatment to a daily dose of duetetrabenazine administered twice daily, which was approximately 30% to 50% of the previous total daily dose of tetrabenazine.

[0469] result Dosage and efficacy. Considering differences in previous therapies and the expected changes in chorea control after initiation of dutetrabenazine therapy in the two cohorts, efficacy data are summarized separately for these two groups. Data from the two cohorts are provided below up to week 15. Since this trial is ongoing, data from subsequent weeks are still being collected and analyzed, and the number of patients included in the results is too small to draw meaningful conclusions at this stage.

[0470] Dose-switch cohort. The mean dose of TBZ at baseline was 42 mg, and the mean dose of deutetrabenazine after an overnight switch was 20 mg. The mean daily dose of deutetrabenazine after switching from TBZ is given in Table 15 below.

[0471] [Table 15]

[0472] Dosage-rollover cohort. The mean daily dose of deutetrabenazine after washout and the initial dose of 6 mg / day are given in Table 16 below.

[0473] [Table 16]

[0474] Total Maximum Chorea (TMC)-Switch Cohort. One week after switching to deutetrabenazine, while subjects were still receiving their initial total daily dose of deutetrabenazine, the mean total chorea score decreased by approximately 1 point from baseline (mean ± standard error [SE] change from baseline was -0.72 ± 2.6), indicating that deutetrabenazine maintained chorea control in these subjects. A subset of 35 subjects with chorea were also assessed 4 weeks after switching to deutetrabenazine. In this set of subjects, the mean (±SE) change from baseline was -0.7 ± 3.0 at week 4, providing further evidence of maintained chorea control. In addition, data from 21 patients became available at week 8; these data showed a change from baseline of -1.9 ± 3.5 units on the TMC score, and -1.2 ± 4.1 units at week 15. The results are given in Table 17 below. A summary of the observed mean chorea scores and the mean daily doses of tetrabenazine or deutetrabenazine corresponding to the chorea scores is provided in Figure 6.

[0475] [Table 17]

[0476] Total maximum chorea (TMC)-rollover cohort. At week 2, a statistically significant mean (SD) decrease of 1.9 (3.0) units from baseline was observed (p<0.0001). This effect persisted until week 15, at which point the mean (SD) decrease from baseline was 4.5 (5.0) units (p=0.0001). These results are consistent with those observed for DTBZ in First-HD. The results are given in Table 18 below.

[0477] [Table 18]

[0478] Transmuscular Score (TMS) - Switch Cohort. Furthermore, overall motor function as assessed by TMS was maintained after dose conversion and was expected to improve at week 8, as indicated by the mean (SD) change from baseline at -3.7 (7.8) TMS. The results are given in Table 19 below.

[0479] [Table 19]

[0480] Figure 7 provides an overview of the observed changes in the mean chorea score and the mean daily doses of tetrabenazine or duetetrabenazine corresponding to the chorea score.

[0481] Total Motor Score (TMS) - Rollover Cohort. A statistically significant mean decrease in TMS from baseline was observed as early as week 2 (3.9 units; p<0.0001) and persisted until week 15 (8.0 units; p=0.0001). The results are shown in Table 20 below.

[0482] [Table 20]

[0483] The fact that the mean TMS improvement (-3.7 units at week 8 in the switch cohort and -8.0 units at week 15 in the rollover cohort) was larger in magnitude than the mean TMC score improvement (-1.9 units at week 8 in the switch cohort and -4.5 units at week 15 in the rollover cohort) suggests that DTBZ treatment benefits not only chorea reduction but also other motor symptoms of HD.

[0484] Other deuterium-substituted tetrabenazines and barbenazines are expected to be effective in treating chorea, Huntington's disease, and other symptoms associated with other movement disorders, as well as involuntary movements in general.

[0485] Adverse events. DTBZ was generally well tolerated, and safety outcomes in both the rollover and switch cohorts were consistent with the safety profile observed in First-HD.

[0486] In the rollover cohort, 39 subjects (52.0%) experienced adverse events (AEs), which were rated as mild or moderate in 36 of these subjects (92.3%). The most common AEs in the rollover cohort were falls (10 subjects, [13%]), drowsiness (6 subjects, [8%]), depression (6 subjects, [8%]), and insomnia (6 subjects, [8%]). A similar percentage of subjects in the rollover cohort experienced AEs from day 1 to week 8 (45.3%) compared to week 8 to the visit cutoff day (43.2%). Five subjects had AEs that resulted in dose reduction or dose discontinuation. Three subjects experienced severe AEs (anxiety, major depression, suicidal ideation, dehydration, encephalopathy, and suicidal depression), one of which (major depression) resulted in withdrawal from the study. Furthermore, three participants withdrew from the study due to adverse events (AEs: exacerbation of chorea, suicidal ideation, and depression).

[0487] In the switch cohort, 21 subjects (56.8%) experienced at least one adverse event (AE), which was rated as mild to moderate in 20 of the 21 subjects (95.2%). The most common AEs in the switch cohort were drowsiness (9 subjects [24%]), anxiety (3 subjects [8%]), and falls (3 subjects [8%]). The majority of these common events occurred during the first 8 weeks of the study (22 switch subjects reached week 8 via the visit cutoff day). The most common AEs occurred at similar rates from day 1 to week 1, from week 2 to week 4, and from week 5 to week 8. There were no adverse events of chorea or exacerbation of chorea during the reporting period, including week 1 after conversion from tetrabenazine to duetetrabenazine. Two subjects experienced serious AEs (pneumonia and dehydration), no subjects withdrew from the study due to AEs, and four subjects had AEs resulting in dose reduction or dose discontinuation.

[0488] In subjects with impaired CYP2D6 metabolism (including those using potent CYP2D6 inhibitors and those with CYP2D6 deficiency), the overall incidence of adverse events (AEs) did not significantly increase.

[0489] Table 21 below summarizes the most frequent adverse events (AEs) that occurred during treatment, defined as events occurring in at least 4% of subjects over the entire treatment period in either cohort. In the rollover cohort, the most common AEs over the entire treatment period were falls (10 subjects [13.3%]), drowsiness (6 subjects [8.0%]), depression (8 subjects [10.7%]), and insomnia (6 subjects [8.0%]). In the switch cohort, the most common AEs over the entire treatment period were falls (3 subjects [8.1%]), drowsiness (9 subjects [24.3%], but mostly transient and did not require dose adjustment), depression (8 subjects [10.7%]), and anxiety (3 subjects [8.1%]). The types of common adverse events observed were consistent with those observed with dutetrabenazine treatment in First-HD. Falls are difficult to assess in this study population with chorea and HD; the majority of falls were not considered to be related to the study drug.

[0490] [Table 21]

[0491] Further safety assessment criteria. Safety scales were incorporated into the study design to monitor asymptomatic toxicity associated with dutetrabenazine treatment. These included observations and changes in UHDRS, SDQ, UPDRS Dysarthria Questionnaire, Barnes Sitting Impairment Rating Scale (BARS), HADS, Epworth Sleepiness Scale (ESS), Columbia Suicide Severity Rating Scale (C-SSRS), and Montreal Cognitive Assessment (MoCA(C)). Overall analysis of safety scales showed no increased risk associated with dutetrabenazine treatment up to week 28 as of the visit cutoff date of this study. Eight rollover patients showed a clear decline in two of the four cognitive assessment criteria (MoCA and speech fluency task) at week 28. These changes were often associated with AEs (e.g., sleepiness, fatigue, urinary tract infection) and were typically not associated with decreased performance on functional assessment criteria. No clinically relevant changes in vital signs, ECG, or laboratory assessments were observed during the study. Regarding body weight, from baseline to week 15, body weight increased in the rollover cohort and changed minimally in the switch cohort. After week 15, both cohorts showed a tendency toward weight loss at week 28 (rollover, 1.4 kg; switch cohort, 1.9 kg), however, the decrease in the number of subjects reaching the week 28 milestone limits the interpretation of these results.

[0492] In summary, the results of this trial support dutetrabenazine as an effective treatment option with a favorable safety profile for the treatment of chorea associated with hemodialysis (HD). The results support the safety of an overnight switch to dutetrabenazine at a dose matched to the AUC predicted from the TBZ, which can be achieved without loss of chorea control.

[0493] Tardive dyskinesia An open-label, single-arm study was conducted in males and females with moderate to severe drug-induced tardive dyskinesia (TD) to evaluate the safety and tolerability of long-term maintenance therapy with deutetrabenazine and to assess the efficacy of deutetrabenazine in reducing the severity of abnormal involuntary movements in TD.

[0494] Study design. The patient eligibility criteria included: at least 18 years of age; successful completion of a previous deutetrabenazine-controlled trial for the treatment of moderate to severe TD; a history of dopamine receptor antagonist use for at least 3 months (or 1 month for subjects aged 60 or older); a clinical diagnosis of TD and having symptoms for at least 3 months; for subjects with an underlying mental disorder, • No change in mental state with psychoactive medication (45 days for antidepressants) for more than 30 days prior to screening; • Subjects receiving long-acting (depot) medications were on stable therapy (dosage, frequency) for more than 3 months prior to screening; and • The study includes mental health professionals who are aware of the subject's participation in the study and do not anticipate any changes to the subject's treatment regimen (medication, dosage, frequency) in the next three months; • A history of adhering to prescription medications; the ability to swallow the entire study drug; the ability to live in a stable environment, have adequate supervision when necessary to adhere to all study procedures, attend all study visits, and safely participate in the study; sufficient reading comprehension to understand the assessment scales completed by the subject; if a subject is a woman of childbearing potential and sexually active, she agrees to use one of the following acceptable methods of contraception from screening to completion of the study: • A well-equipped IUD or intrauterine contraceptive system for at least three months prior to screening; • The subject or partner uses a spermicide and blockade method from screening to completion of the test; • The partner has undergone a vasectomy demonstrated within six months prior to registration; or • Stable hormonal contraception (approved oral, transdermal, or depot regimen) for at least three months prior to screening.

[0495] Exclusion criteria included: the subject had received tetrabenazine within 7 days of baseline, or any of the following drugs within 30 days of baseline: reserpine, alpha-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of baseline), and drugs with potent anticholinergic activity (trihexylphenidyl, benzotropin, orphenadrine, procyclidine, and biperiden), metoclopramide, promethazine, prochlorperazine, stimulants (i.e., methylphenidate, amphetamine / dextroamphetamine, lisdexamfetamine, etc.), monoamine oxidase inhibitors, and (MAOIs), levodopa, or dopamine agonists; the subject had a neurological condition other than TD that could interfere with the assessment of dyskinesia severity; or the subject had severe untreated or poorly treated sperm at baseline. Medical condition; active suicidal ideation at baseline; any of the following within 6 months of baseline: a prior intention to act on suicidal ideation with a specific plan, regardless of the level of bilaterality at the time of the suicidal thought (positive response to question 5 on the C-SSRS); prior preparatory behavior to commit suicide or commit suicide; or a prior actual, interrupted, or aborted suicide attempt; a score of 11 or higher on the depressive subscale of the Hospitalization Anxiety and Depression Scale (HADS) at baseline; the subject has a developmental disorder or evidence of dementia; the subject has a precarious or serious medical condition at baseline; a history of or presence of violent behavior (within 3 months); a QTcF value greater than 450 ms (male) or greater than 460 ms (female), or greater than 480 ms (right bundle branch block [RBBB]) on a 12-lead electrocardiogram (ECG) at baseline; 2.5 ms above the upper limit of normal (ULN).Evidence of liver impairment at screening, indicated by aspartate transaminase (AST) or alanine aminotransferase (ALT) levels greater than 5 times, alkaline phosphatase (ALP) or total bilirubin (TBil) levels greater than 2 times ULN (however, subjects with Gilbert's syndrome are eligible to participate if approved by the medical monitor, and subjects with abnormalities in two or more of these analytes (AST, ALT, ALP, TBil) must be approved for enrollment by the medical monitor), and prothrombin time prolonged beyond 4 seconds. ; Positive for hepatitis B surface antigen (HBsAg); evidence of significant renal impairment at screening, indicated by a creatinine clearance of less than 50 mL / min as estimated by the Cockroft-Gault formula; known allergy to either tetrabenazine or deutetrabenazine; participation in an investigational drug or device trial (other than an eligible deutetrabenazine trial) and receiving the investigational drug within 30 days (or 5 drug half-lives) of baseline (whichever is longer); pregnancy or lactation at baseline; and presence of illegal drug use at baseline.

[0496] Dose regimen. Dutetrabenazine regimen tablets were provided in dose strengths of 6, 9, 12, 15, and 18 mg. During dose adjustment / titration, dutetrabenazine was supplied weekly in blister cards. During long-term treatment, dutetrabenazine was supplied in 30-count bottles. The study drug was administered as follows: All treatment regimens were administered twice daily (BID) with meals, approximately 10 hours apart during the day. The starting dose was 12 mg / day (6 mg BID) of dutetrabenazine, regardless of prior treatment in the parent study. Assignments of prior treatment from the parent study remained blinded. The maximum total daily dose of dutetrabenazine was 48 mg / day (24 mg BID) unless the subject was receiving a potent CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion), but if receiving such an inhibitor, the maximum total daily dose was 36 mg / day. The maximum daily dose of 36 mg / day was administered as one tablet in BID, while daily doses of 42 mg / day and 48 mg / day were administered as two tablets in BID. During the titration period, the dose of deutetrabenazine should be increased on a weekly basis in 6 mg / day increments until: 1) dyskinesia is well controlled; 2) the subject experiences a clinically significant adverse event (AE) as defined in the protocol (related to the study drug and defined as a) moderate to severe in severity, or b) meeting the criteria for a standard adverse event (SAE); or 3) the maximum tolerable dose is reached. If a subject experiences a clinically significant AE attributable to deutetrabenazine, the principal investigator determined whether dose reduction or discontinuation was necessary.

[0497] Long-term treatment. For all patients participating in the long-term treatment period, the dose of dutetrabenazine may be adjusted (upward or downward) in increments of 6 mg per day, as needed, to optimize dyskinesia control while minimizing adverse events (AEs). However, such dose changes should not occur more frequently than once a week.

[0498] Titration period (up to 6 weeks). Subjects who successfully completed the parent study were eligible to enroll in this study after a 1-week washout period and final evaluation. When subjects discontinued the study drug or placebo for 1 week, they underwent dutetrabenazine dose titration in this study. During titration, the principal investigator consulted with the subjects to determine when a sufficient level of dyskinesia control was achieved. The dose of dutetrabenazine was adjusted (up or down) in increments of 6 mg per day up to once a week until a clinically significant adverse event (a) of moderate or severe severity, or (b) a serious adverse event occurred, or until the maximum tolerable dose was reached. If a subject experienced a clinically significant AE attributable to dutetrabenazine, the principal investigator determined whether dose reduction or discontinuation was necessary. To assess safety and establish a well-tolerated dosage of the study drug that adequately controlled dyskinesia, subjects received telephone contact during clinical visits in weeks 1 and 2. Subjects entered a long-term treatment period after week 2, but titration was continued until week 6 to optimize the dosage.

[0499] Long-term treatment period (up to 52 weeks). During the long-term treatment period, subjects will continue titration for up to 6 weeks. During this period, all subjects will receive telephone contact at weeks 3 (the first week of the long-term treatment period) and 5 for safety and dyskinesia control evaluation, and will return to the clinic at weeks 4, 6, 15, 28, 41, and 54. Subjects who have not achieved adequate control of dyskinesia and a well-tolerated dose level by the week 6 visit should be contacted by an unscheduled visit or telephone to further adjust their dose upward or downward. Clinical interaction for dose adjustment should alternate between telephone contact and clinical visits. During the long-term treatment period, further dose adjustments of dutetrabenazine may be made as needed, but not more frequently than weekly, and only in increments of 6 mg per day. Dose adjustments should be based on all available information, including reports of AE and dyskinesia control by subjects and caregivers (where preferred), and, where available, information from assessment scales and safety assessments.

[0500] Post-treatment safety follow-up. All subjects will discontinue the study drug at the visit in week 54 and return for a final clinical visit in week 55 to evaluate safety, dyskinesia control, and motor function. During this one-week washout period, subjects should not take any prohibited concomitant medications. Subjects will also receive a follow-up telephone contact in week 58, four weeks after the last dose of the study drug, to evaluate adverse events and concomitant medication use.

[0501] Safety evaluation items. Safety and tolerability will be evaluated throughout the study by monitoring the following parameters: adverse events (AEs), laboratory tests, physical examination, vital signs, 12-lead ECG, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Tests), Barnes Sitting Disorder Rating Scale (BARS), Hospitalization Anxiety and Depression Scale (HADS), Columbia Suicide Severity Rating Scale (C-SSRS), Epworth Sleepiness Scale (ESS), and Montreal Cognitive Assessment (MoCA(C)).

[0502] Efficacy assessment items. To assess efficacy, the following scales were used or will be used: Changes in the Abnormal Involuntary Motor Scale (AIMS) score (items 1 to 7) from baseline to the end of long-term therapy (week 54), as assessed by blinded central video rating; Based on the clinically comprehensive impression of change (CGIC), the proportion of subjects who were treated successfully at the end of long-term therapy (week 54) (treatment success is defined as a significant or very significant improvement); the change in modified head and neck dystonia (CDQ-24) score from baseline to the end of long-term therapy (week 54) in this study; the proportion of subjects whose AIMS score decreased by 50% or more from baseline to the end of long-term therapy (week 54) in this study; the proportion of subjects who were treated successfully at the end of long-term therapy (week 54) (treatment success is defined as a significant or very significant improvement) based on the patient's comprehensive impression of change (PGIC); the percentage change in AIMS score from baseline to the end of long-term therapy (week 54) in this study; and the cumulative proportion of respondents who showed improvement ranging from 10% improvement from baseline to 90% improvement from baseline, in 10-point increments, based on the change in AIMS score from baseline to the end of long-term therapy (week 54) in this study, as assessed by blinded central video assessment.

[0503] Results. The results are shown in Figure 9, which indicate that by week 6 of the trial, more than 50% of the subjects had shown significant or very significant improvement according to PGIC and CGIC.

[0504] ARM-TD Further clinical trials, the Aim to Reduce Movements in Tartive Dyskinesia (ARM-TD) trial, were designed and conducted to evaluate the efficacy of SD-809 (dutetrabenazine) in the treatment of moderate to severe tardive dyskinesia. The ARM-TD trial was a 1:1 randomized, double-blind, placebo-controlled, parallel-group trial involving a total of 117 patients with moderate to severe tardive dyskinesia (104 patients completed the trial).

[0505] Subjects were screened for inclusion in the study as follows: The patient inclusion criteria included: age 18–75 years, comprehensive; history of dopamine receptor antagonist use for at least 3 months (or 1 month for subjects 60 years or older); clinical diagnosis of TD and presence of symptoms for at least 3 months prior to screening; TD symptoms being troublesome or causing functional impairment to the subject; at screening and baseline visit, the subject having moderate or severe abnormal motor function as determined by the principal investigator based on AIMS item 8 and a combined motor AIMS score of 6 or higher (based on items 1 through 7) as assessed by the principal clinical trial physician; for subjects with underlying psychosis, the subject being mentally stable for at least 30 days (45 days for antidepressants) prior to screening and taking psychoactive drugs (but not limited to neuroleptics, benzodiazepines, antipsychotics). No changes in medications (including convulsants and mood stabilizers); subjects receiving long-acting (depot) medications have been on stabilizing therapy (dosage, frequency) for at least three months prior to screening; and subjects have a mental health professional who is aware of their participation in the study and does not anticipate any changes to their treatment regimen (medication, dosage, frequency) in the next three months; a history of adherence to prescription medications; the ability to swallow the entire study drug; documented informed consent; subjects are in good general health, live in a stable environment, are expected to complete all study assessments, have sufficient supervision when necessary to comply with all study procedures, attend all study visits, and participate safely in the study; subjects have sufficient reading comprehension to understand the assessment scales completed; and women of childbearing potential who are sexually active agree to use an acceptable method of contraception from screening to completion of the study.

[0506] Exclusion criteria included: a score of 11 or higher on the depressive subscale of the Hospitalization Anxiety and Depression Scale (HADS) at screening or baseline; evidence of developmental disorder or dementia; unstable or serious medical condition at screening or baseline; history of or presence of violent behavior (within the past 3 months); QTcF values ​​exceeding 450 ms (male) or 460 ms (female), or 480 ms (right bundle branch block [RBBB]) on a 12-lead ECG at screening; AST or ALT exceeding 2.5 times the upper limit of normal (ULN), or ALP or total bilirubin exceeding 2 times the ULN (subjects with Gilbert's syndrome are eligible to participate if approved by the medical monitor, but abnormalities in two or more of these AST, ALT, ALP, or TBil require approval by the medical monitor for enrollment), or prolonged prothrombin time exceeding 4 seconds, or evidence of liver impairment at screening, as indicated by a positive HBsAg test; Evidence of significant renal impairment at screening, indicated by a creatinine clearance of less than 50 mL / min as estimated by the Cockroft-Gault formula; a known allergy to either tetrabenazine or duetetrabenazine; the subject participating in the investigational drug or device trial and receiving the investigational drug within 30 days (or 5 drug half-lives) of screening (whichever is longer); being pregnant or lactating at screening or baseline; a known history of illicit drug use at screening; a history of alcohol or substance abuse in the preceding 12 months, as defined in DSM-V, or the subject being unable to control substance abuse throughout the trial; and a positive drug urine test at screening or baseline (for amphetamines, barbiturates, benzodiazepines, phencyclidine, cocaine, or opioids), unless the subject is receiving a stable dose of benzodiazepines.

[0507] Medication. Enrolled patients received either deutetrabenazine or placebo and titrated over a 6-week course in increments of 6 mg / day per week, from a starting dose of 6 mg of deutetrabenazine (providing a total (α+β)-HTBZ AUC equivalent to 12.5 mg of tetrabenazine, as in previous studies) up to an optimal dose of 12–48 mg / day. The drug was then administered at that dose for another 6 weeks over a total of 12 weeks of treatment, followed by a 1-week washout period. Randomization to each group was 1:1 and stratified by baseline use of a dopamine receptor antagonist (against not currently taking one). Deutetrabenazine tablets or placebo were supplied as 6, 9, 12, 15, and 18 mg tablets and administered morning and evening (10-hour intervals recommended; minimum 6-hour intervals) with meals in a BID (Bedtimes-Independence Day). If a subject experienced a clinically significant adverse event, a dose suspension of up to 1 week was permitted.

[0508] Study Objectives and Endpoints. The objectives of the study were 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 dutetrabenazine in subjects with drug-induced tardive dyskinesia. The primary efficacy endpoint was the change in AIMS score (items 1 to 7) from baseline to week 12, as assessed by blinded central video assessment. The baseline AIMS score was defined as the assessment on day 0 for each subject. AIMS consisted of items administered and scored by 12 physicians. Items 1 to 10 were assessed on a fixed 5-point scale and consisted of the following: Items 1-4 assess oral and facial movements; Items 5-7 deal with limb and trunk dyskinesia; Items 8-10 deal with the overall severity as determined by the examiner, and the patient's subjective perception of movement and related pain; and Items 11-12 are yes / no questions regarding problems related to teeth and / or dentures, and such problems can be mistaken for dyskinesia.

[0509] A total score derived from items 1 through 7 (oral and facial, limb, and trunk movements) is calculated and can represent the observed movements, with higher scores indicating more severe dyskinesia. Item 8 can be used as an overall severity index; items 9 and 10 provide further information regarding the patient's inability and self-awareness; and items 11 and 12 provide information that may be useful in determining lip, jaw, and tongue movements.

[0510] The key secondary endpoints are: 1) the proportion of subjects with treatment success at week 12, based on the clinically global impression of change (CGIC); 2) the proportion of subjects with treatment success at week 12, based on the patient's global impression of change (PGIC); and 3) the change in the Modified Head and Neck Dystonia Questionnaire (CDQ-24) from baseline to week 12. In relation to previous studies, treatment success based on PGIC / CGIC can be defined as a significant or very significant improvement on a 7-point Likert scale, ranging from very significant deterioration to very significant improvement at week 12. The CDQ-24 is a disease-specific quality of life questionnaire developed for use in patients with head and neck dystonia, including both cervical dystonia (CD) and blepharospasm (BPS). The CDQ-24 was selected for use in this study because it includes areas relevant to TD, such as scarring, mental stability, pain, activities of daily living, and social / family life, in addition to CD and BPS. For this study, the CDQ-24 was modified so that the questions directly focus on the impact of TD (the opposite of CD / BPS) on quality of life.

[0511] Further secondary endpoints included: 1) the percentage change in AIMS score (central rating) from baseline to week 12; 2) the cumulative percentage of respondents with response levels ranging from a 10% improvement from baseline to a 90% improvement from baseline, in 10-point increments, based on the change in AIMS score (central rating) from baseline to week 12; and 3) the change in AIMS score (items 1 through 7) from baseline to week 12, as assessed by local evaluators, with the baseline AIMS score defined as the day 0 assessment for each subject.

[0512] Finally, in each clinical setting, the principal investigator with experience in evaluating motor impairment was responsible for confirming the diagnosis of TD, conducting all clinical evaluations, and making decisions regarding adjustments to the investigational drug dosage. Safety was also monitored using adverse event reporting and other evaluation criteria, including, but not limited to, UPDRS, BARS, HADS, C-SSRS, ESS, and MoCA.

[0513] Measurements and statistics. Digital video recordings of AIMS assessments performed at all clinic visits (screening, baseline, weeks 2, 4, 6, 9, and 12) were rated by a pair of central raters blinded to AIMS scores for treatment group, video sequence, and the investigator's AIMS score. Analysis was performed using a linear mixed model (MMRM) of repeated measures, including change in AIMS score as the dependent variable. This model included fixed effects for treatment group, time points (five levels: weeks 2, 4, 6, 9, and 12), treatment group interactions, and randomization stratification variables. Using an unstructured covariance model, a primary analysis was performed comparing the dutetrabenazine group and the placebo group at week 12 with a two-tailed test at a 5% significance level.

[0514] Efficacy results. The data in the top row showed that the trial met its primary endpoint. Patients taking deutetrabenazine achieved a clinically meaningful effect, with a 3.0-point improvement in the AIMS score from baseline to the end of therapy compared to 1.6 points in the placebo group (p=0.0188). Furthermore, secondary endpoints were numerically favorable to deutetrabenazine. The results are given in Table 22.

[0515] [Table 22]

[0516] Safety Results. The trial also demonstrated a favorable safety and tolerability profile for deutetrabenazine, including low rates of depression, drowsiness, insomnia, and orthostatic hypotension. Serious adverse events (SAEs) (4 patients [6.9%] in deutetrabenazine compared to 6 patients [10.2%] in placebo; none of the SAEs were associated with the treatment) or adverse events leading to discontinuation (1 patient [1.7%] compared to 2 patients [3.4%]) were less frequent in patients receiving deutetrabenazine than in placebo. Neuropsychiatric adverse events in this patient population were rarely associated with SD-809 treatment compared to placebo and included drowsiness / sedation (9 patients [15.5%] vs. 6 patients [10.2%]), insomnia (4 patients [6.9%] vs. 1 patient [1.7%]), and orthostatic hypotension (3 patients [5.2%] vs. 0 patients [0.0%]). Depression / melancholy was reported by one patient in each treatment group, and suicidal ideation was reported by one patient in the placebo group, compared to none in the SD-809 group. Three patients discontinued the study due to adverse events (one in the deutetrabenazine group compared to two in the placebo group). For all other adverse events reported in the study, the rates in the deutetrabenazine group were similar to or lower than those in the placebo group. Results, including adverse events observed in three or more subjects, are shown in Table 23 below.

[0517] [Table 23]

[0518] Based on the studies disclosed herein, deutetrabenazine, other deuterium-substituted tetrabenazines, and valbenazines are expected to be effective in treating tardive dyskinesia as well as other movement disorders and symptoms such as general dyskinesia, dystonia, ballism, akinesia, and parkinsonism, and the drug regimens and methods disclosed herein are expected to provide significant patient benefits.

[0519] Tourette syndrome Tourette syndrome (TS) is a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics, which, according to DSM-V criteria, first appear in early childhood before the age of 18. Several studies have been, or could have been, used to demonstrate the efficacy and tolerability of dutetrabenazine in alleviating symptoms associated with TS, including motor and vocal tics.

[0520] Open-label pilot study of safety and efficacy in TS patients An open-label pilot study was conducted to 1) evaluate the safety and tolerability of treatment with deutetrabenazine, and 2) evaluate the efficacy of deutetrabenazine in suppressing motor and vocal tics in TS.

[0521] Study Design. The patient inclusion criteria (as of screening, unless otherwise noted) included: age 12–18 years, comprehensive; diagnosis of TS according to DSM-V and presence of motor and vocal tics within 3 months prior to screening; overall tic score of 19 or higher on the YGTSS; TS-CGI score of 4 or higher (consistent with moderate disorder); tic severity and frequency were stable for at least 2 weeks; able to swallow the entire study drug; willingness to adhere to the medication regimen and all procedures; and as demonstrated by medical and mental history and physical and neurological examinations. In good general health; documented informed consent (of the subject and parent / guardian); and the subject, a woman of childbearing potential, agrees to use an acceptable method of contraception until completion of the trial, including abstinence, a well-equipped IUD or intrauterine system, for at least three months prior; the subject or partner uses a spermicide with a blocking method (e.g., condom, diaphragm, or cervical cap); the partner has undergone a demonstrated vasectomy within six months prior to enrollment; and stable hormonal contraception (approved oral, percutaneous, or depot regimen) for at least three months prior.

[0522] Exclusion criteria (as of screening or baseline, unless otherwise noted) included: severe untreated or poorly treated psychosis, such as depression, schizophrenia, or bipolar disorder (however, subjects receiving antidepressant therapy if on a stable dose for at least the preceding eight weeks may be enrolled); prior intentions to act on suicidal ideation with a specific plan, regardless of the level of bilaterality at the time of the suicidal ideation (positive response to question 5 on the Columbia Suicide Severity Rating Scale [C-SSRS]); prior preparations History of suicidal thoughts or behaviors, including activities or actions, or previous actual, interrupted, or discontinued suicide attempts; whether the subject received any of the following concomitant medications within 14 days prior to screening or baseline: tetrabenazine, nerve relaxants (oral or depot, typical and atypical; depot within 3 months of screening), guanfacine or clonidine (within 7 days of screening or baseline), clonazepam, topiramate, metoclopramide, monoamine oxidase inhibitors (MAOIs), levodopa or Dopamine agonists, benzodiazepines such as reserpine (within 21 days of screening or baseline), botulinum toxin (within 3 months of screening or baseline); subjects being treated with deep brain stimulation for tic control; below-average intelligence or cognitive impairment in the opinion of the principal investigator; progressive or degenerative neurological or structural impairment of the brain; subjects receiving more than one medication for the treatment of each concomitant behavioral symptom; subjects requiring treatment with a drug known to prolong the QT interval (however, shita Lopram and escitalopram are permissible if administered according to the approved label; QTcF values ​​greater than 440 ms on a 12-lead electrocardiogram (ECG); known allergies to any of the components of the study drug; participation in a study drug or device trial within 30 days (or 5 drug half-lives) of screening (whichever is longer); pregnancy or lactation; current use of illicit drugs; and a history of alcohol or substance abuse in the previous 12 months as defined in DSM-V, or inability to control substance abuse throughout the trial.

[0523] Participants completing the study received treatment with the study drug for a total of eight weeks and underwent a four-week safety follow-up after treatment. Throughout the study, independent assessors evaluated tic severity using the Yale Global Tic Severity Scale (YGTSS) and the impact of tics using the TS Clinical Global Impression (TS-CGI) scale. The independent assessors had no knowledge of the participants' clinical care, including drug or adverse event (AE) reporting.

[0524] Dose regimen. The study drug was available in five dose intensities: 6, 9, 12, 15, and 18 mg, all of which were identical in size, shape, and color (white). Eligible subjects were assigned to treatment with deutetrabenazine and titrated over 6 weeks to a dose level of the study drug that adequately suppressed tics and was well tolerated (i.e., the optimal dose). Subjects then maintained that dose level throughout the treatment period. Subjects receiving CBIT (Comprehensive Behavioral Intervention for Tics) therapy were permitted to participate as long as the therapy was stable / progressing for at least 4 weeks prior to screening and was expected to remain stable throughout the duration of the study. The study drug was administered as follows: All treatment doses were administered with meals. A daily dose of 6 mg was given once daily in the morning, and daily doses of 12 mg or more were given in divided doses twice daily, approximately 10 hours apart. The starting dose was 6 mg of deutetrabenazine in the morning. The dose of the study drug was 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. In this study, the maximum total daily dose of dutetrabenazine at visits from week 5 onward was 36 mg (18 mg twice daily [BID]).

[0525] Screening / baseline visit. After obtaining informed consent, subjects who met the selection criteria underwent a comprehensive evaluation including physical and neurological examinations. Subsequently, subjects underwent baseline assessments of tic severity (conducted by an independent assessor) and medical comorbidities. Following this assessment, subjects who continued to meet the selection criteria were offered dutetrabenazine, treatment was initiated on day 1, and a baseline visit was scheduled for the following day.

[0526] The titration period was 6 weeks. Participants and their parents / guardians communicated weekly with the clinical research staff, either by telephone or clinic visit, until week 6 of the titration period, to assess safety and establish a dutetrabenazine dose that adequately suppressed tics and was well-tolerated. Safety assessments during titration included monitoring of vital signs, monitoring of adverse events, and assessment of scales related to depression, suicidal ideation, and behavior. In-person trial visits were scheduled for weeks 2 and 4 after the start of therapy, and telephone contacts were scheduled for weeks 1, 3, 5, and 6 after the start of therapy to assess tic suppression and adverse events. The YGTSS and TS-CGI were assessed by independent evaluators. The principal investigator, in consultation with the participants and their parents / guardians, determined when an adequate level of tic suppression was achieved. The dose of dutetrabenazine was increased on a weekly basis until the subject experienced a clinically significant adverse event (AE) as defined in the protocol (AEs related to the study drug that (1) are of moderate or severe intensity, or (2) meet the criteria for a serious adverse event [SAE]), or until the maximum tolerable dose was reached. Dose adjustments could be made up to that point, including by telephone in week 5, but if a stable dose was reached before then, the subject continued that dose for the remainder of the titration period and through maintenance dosing. Once sufficient tic suppression was achieved, the dose of the study drug was not further increased. If a subject experienced a clinically significant AE attributable to the study drug, the principal investigator used their judgment to determine whether dose reduction or discontinuation was necessary. Dose adjustments were based on all available information, including reports from the subject and parent / guardian regarding AEs and tic suppression, clinical assessments of safety and efficacy by the principal investigator, and information from rating scales. At the end of the titration period, the subject's dose was established for the maintenance period.

[0527] Maintenance period (2 weeks). Participants continued to receive the maintenance dose for the next two weeks, although dose reduction due to adverse events was permitted. Participants returned to the clinic at week 8 for a complete assessment including physical and neurological examinations and performance on all assessment scales, including YGTSS and TS-CGI, as assessed by an independent evaluator. Participants discontinued the study drug at the week 8 visit.

[0528] Follow-up (4 weeks). Participants returned one week after the week 8 visit for safety and tic suppression assessment. Participants were also followed up by telephone contact four weeks after the last dose of the study drug. Participants who completed the study were potentially eligible to participate in any long-term safety studies that were conducted.

[0529] Pharmacokinetics. A PK sub-study was conducted to evaluate the pharmacokinetics of deutetrabenazine and its metabolites in up to 9 of the 21 registered subjects. Subjects participating in the PK sub-study underwent continuous PK blood sampling over a 6-hour period following administration during the 8th week visit. For subjects not participating in the PK sub-study, a single PK sample was obtained in the 8th week during blood collection for clinical testing.

[0530] Safety evaluation items. Safety and tolerability were assessed throughout the trial by monitoring the following parameters: adverse events (AEs), laboratory tests, physical examination, vital signs, 12-lead ECG, Columbia Suicide Severity Rating Scale (C-SSRS), Beck Depression Questionnaire, second version (BDI-II), and the Pediatric Yale-Brown Obsessive-Compulsive Scale (CY-BOCS).

[0531] Efficacy evaluation criteria. The following evaluation criteria were used to assess efficacy: Yale Global Tic Severity Scale (YGTSS), YGTSS Total Tic Severity Score (TTS), YGTSS General Severity Score (GSS), Clinical General Impression of Tourette Syndrome (TS-CGI), and General Impression of Change in Tourette Syndrome Patients (TS-PGIC).

[0532] Results. Initial results indicate that deutetrabenazine is effective in treating tics associated with Tourette syndrome. A consistent trend of improvement was observed from baseline to the end of the 8-week treatment period in motor tics, vocal cord tics, overall tic severity, and Yale General Overall Tic Severity. This resulted in a mean change of -10.4 units in overall tic severity. Furthermore, discontinuation of treatment after 8 weeks resulted in a slight increase in tics. The results are given in Table 24 below; ND indicates no data.

[0533] [Table 24A]

[0534] [Table 24B]

[0535] Furthermore, preliminary results show improvements in several other relevant assessment criteria. In PGIC, a mean improvement of 1.8 points was observed (on the 7-point scale above, 1 = minimal improvement, 2 = significant improvement, 3 = very significant improvement), suggesting that patients improved overall after 8 weeks of treatment (approximately 75% showed significant or very significant improvement). In TS-CGI, a mean improvement from a baseline of 4.7 to 3.7 at week 8 was observed (on the 7-point scale, lower is better). Finally, the adverse event profile was considered to be consistent overall with previous trials.

[0536] Deuterabenazine, other deuterium-substituted tetrabenazines, and valbenazines are effective in treating Tourette syndrome and other movement disorders and symptoms such as tics, stereotypics, sitting incapacitation, dyskinesia, and restless legs syndrome, and the drug regimens and methods disclosed herein are expected to provide significant patient benefits.

[0537] A 12-week randomized phase 2 / 3 trial on the safety and efficacy of TS in patients. Objective. The primary objective of this study is to evaluate the efficacy of deutetrabenazine in reducing motor and vocal tics associated with TS; a secondary objective of this study is to evaluate the safety and tolerability of titration and maintenance therapy with deutetrabenazine.

[0538] Study Design. This is a phase 2 / 3, randomized, double-blind, placebo-controlled, parallel-group trial inviting patients with Tourette's syndrome (TS) and associated tics to participate. The trial includes male and female patients aged 6–16 years (inclusive) with Tourette's syndrome (TS) and associated tics. Patients were randomized and stratified by age at baseline [6–11 years, 12–16 years]. The dose of the study drug for each patient was titrated to an optimal level, and then maintenance therapy was administered at that dose. The total treatment period was 12 weeks. The titration period was 7 weeks, the maintenance period was 5 weeks, followed by a 1-week washout period.

[0539] Study patient eligibility criteria. Patients must meet the following criteria: age 6–16 years at baseline, comprehensive; body weight of at least 44 pounds (20 kg) at baseline; meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) diagnostic criteria for tics, and the patient's active tics are distressing or causing impairment, as judged by the principal investigator, patient, and caregiver / adult; score 20 or higher on the YGTSS at screening and baseline; be able to swallow the entire study drug; the patient and caregiver / adult are committed to the drug regimen and willing to adhere to all study procedures; good overall health as indicated by medical and mental history and physical and neurological examinations; and the nature of the study and its procedures. Patients may be enrolled in the study if they meet all of the following criteria: ability to understand quality and expectation that the trial will be completed as designed (opinion of the principal investigator); informed consent document; and the fact that the male partner of childbearing potential must use contraception (acceptable contraceptive methods are those with a failure rate of less than 1% per year, such as IUDs, oral, implantable, percutaneous, or injectable hormonal contraception, spermicide-assisted blockade, and partner vasectomy) throughout the study period and for 30 days after discontinuation of the study drug, and that the woman / girl of childbearing potential (not surgically infertile (for more than 3 months) by tubal ligation, hysterectomy, or oophorectomy, or congenitally infertile).

[0540] Exclusion criteria: The patient has a neurological disorder other than tics that could obscure the assessment of tics; The patient's primary motor impairment is stereotypic (coordinated movements of repetitive, identical movements) associated with autism spectrum disorder; a confirmed diagnosis of bipolar disorder, schizophrenia, or another mental disorder; clinically significant depression at screening or baseline (however, patients receiving antidepressant therapy may be enrolled if they have been on a stable dose for at least 6 weeks prior to screening (see the list below for prohibited antidepressants)); a history of suicidal intent or related behavior within 2 years of screening; previous intentions to act in accordance with suicidal ideation in a specific plan, regardless of the level of bilaterality, at the time of the suicidal thought; previous suicidal preparatory activities or behaviors; a history of previous actual, interrupted, or discontinued suicide attempts; a first-degree relative who has completed suicide; clinically significant OCD at baseline, in the opinion of the principal investigator, as the primary cause of the disorder; the patient has received a CBIT for TS or a CBT for OCD within 4 weeks of screening; the patient is receiving any of the following concomitant medications for tics within the specific exclusion window of screening: • Within 3 months: Depot nerve relaxant, botulinum toxin, or tetrabenazine; • Within 21 days: Reserpine; • Within 14 days: Monoamine oxidase inhibitors, oral tranquilizers, typical and atypical antipsychotics, metoclopramide, levodopa, and dopamine agonists (Note: Benzodiazepine use is permitted if the primary use is not for tics and the medication has been stable for at least 4 weeks prior to screening; topiramate use (up to 200 mg / day) is permitted if the medication has been stable for at least 4 weeks prior to screening; and guanfacine or clonidine use is permitted if the medication has been stable for at least 4 weeks prior to screening); Treatment with deep brain stimulation, magnetic stimulation, or transcranial direct current stimulation to reduce tics within four weeks of the screening visit; unstable or serious medical conditions at screening or baseline; the patient requiring treatment with drugs known to prolong the QT interval (listed below); QTcF interval values ​​greater than 440 msec on a 12-lead ECG at screening; evidence of liver impairment (indicated by AST or ALT greater than 2.5 times the upper limit of the normal range (ULN) at screening, or ALP or total bilirubin (Tbil) greater than 2 times the ULN at screening, but in patients with Gilbert's syndrome and patients with abnormalities in two or more of the following: AST, ALT, ALP, and Tbil) Patients will not be enrolled in this study if they meet any of the following criteria: eligible to participate if approved by a medical monitor; evidence of clinically significant renal impairment, indicated by serum creatinine greater than 1.5 times the ULN at screening; a known allergy to any of the components of the study drug product; the patient has participated in a study drug or device trial and received the study drug / intervention within 30 days of baseline or within 5 drug half-lives (whichever is longer); are pregnant or lactating; have a history of recognized alcohol or substance abuse in the previous 12 months as defined in DSM-V; have a positive drug urine test result or are unable to control substance abuse throughout the study; or, in the opinion of the principal investigator, meet any of the following DSM-V diagnoses based on the MINI Kid Inventory module performed at screening that make the patient unsuitable for the study.

[0541] Prohibited substances include azithromycin, chloroquine / mefloquine, clarithromycin, domperidone, droperidol, erythromycin, moxifloxacin, sevoflurane, probucol, sparfloxacin, chlorpromazine, aripiprazole, haloperidol, asenapine maleate, roxapine, clozapine, morindone, iloperidone, perphenazine, lurasidone, pimozide, olanzapine, prochlorperazine, olanzapine / fluoxetine, thioridazine, paliperidone, thiothixen, ketiapine, trifluoperazine, risperidone, promethazine-containing compounds, ziprasidone, and tiapride.

[0542] Efficacy endpoints. The primary efficacy endpoint of the study was the change in the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (TTS) from baseline to week 12, with the goal of reducing motor and articulation / vocal tics. Secondary efficacy endpoints were all changes from baseline to week 12 in the Clinical Global Impression of Tourette Syndrome (TS-CGI) score, the Global Impression of Severity in Tourette Syndrome Patients (TS-PGIS) score, and the Physical / Activities of Daily Living (ADL) subscale of the Gilde-Tourette Syndrome - Quality of Life (GTS-QOL).

[0543] Safety evaluation criteria. Safety evaluation criteria include the occurrence of adverse events; observed values ​​and changes from baseline in vital signs; observed values ​​and changes from baseline in the Child Depression Inventory II (CDI-2; parent and self-reported version); observed values ​​in the Child Columbia Suicide Severity Rating Scale (C-SSRS); observed values ​​and shifts from screening for clinically significant abnormal findings in electrocardiogram (ECG) parameters; and observed values ​​and changes from screening in clinical laboratory parameters (hematology, chemistry, and urinalysis).

[0544] Titration period (7 weeks). Patients who are still eligible to participate in the study are randomized at the baseline visit (day 1) and receive 6 mg of the blinded study drug with a meal that evening (i.e., after the study visit).

[0545] 1) Increase the dose of the study drug until the tic is optimally reduced, as determined by the principal investigator in consultation with the patient and caregiver / adult; 2) Increase the dose until the dose is no longer tolerable.

[0546] Maintenance period. At the end of the infusion period, the patient's dose for the maintenance period is established. The patient continues to receive that maintenance dose for the next 5 weeks, but dose reduction due to adverse events is permitted. The patient returns to the clinic at weeks 9 and 12 for safety and efficacy evaluation. At week 12, the patient undergoes a full evaluation, including safety and efficacy evaluation criteria.

[0547] Washout period. All patients discontinue the study drug at the visit in week 12 and return one week later (week 13) for safety and tic reduction evaluation.

[0548] Dose regimen. As discussed above, the study drug is administered once daily as an oral tablet at a starting dose of 6 mg and titrated. Dutetrabenazine tablets are available in the following dose strengths: 6, 9, 12, 15, and 18 mg, and are distinguishable by markings and colors. In all patients, the initial dose of 6 mg is administered in the evenings of days 1 and 2, and the remainder of the first week is administered in the mornings (if the patient weighs less than 40 kg); the entire study drug should be swallowed and taken with a meal; thereafter, a daily dose of 12 mg or more is administered in two divided doses twice daily, with approximately 8-10 hours between doses; there should be a minimum of 6 hours 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 a patient experiences insomnia while taking the initial 6 mg dose in the evening, it may be switched to taking it as a morning dose for two days; after the first week, dose increases should not be made more frequently than every 5 days; and instructions should be provided to ensure that dose decreases, if necessary, should be in increments of 6 mg.

[0549] Blinding and randomization. Patients are randomly assigned to receive treatment with either a 1:1 ratio of dutetrabenazine or a balanced dose of placebo.

[0550] Expected results: In the above studies in patients with Tourette syndrome, administration of dutetrabenazine in tolerable doses of 6–48 mg is expected to reduce overall tic severity, both motor and vocal / articulation tics, impairment, and / or general severity scores, improve quality of life, overall life satisfaction, and / or changes in patient- or clinical overall impression, and improve (lengthen) tic-free intervals. Safety is expected to be consistent with that observed in previous studies.

[0551] Long-term, open-label phase 3 trial of safety and efficacy in TS patients Objective. The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with dutetrabenazine; a secondary objective is to evaluate its efficacy.

[0552] Study design. This study includes male and female patients with Tourette syndrome (TS) and associated tics who have previously completed participation in any of the above clinical trials of deutetrabenazine.

[0553] Screening. Informed consent will be obtained before conducting the study procedure. Patients who have been deprived of the study drug for several months at the time of enrollment and who are medically and mentally stable will undergo the above screening assessment in the randomized trial. To reduce patient burden, some data collected in the above randomized trial will be used to provide corresponding data in this open-label trial. Patients may be rescreened by medical monitor segregation. The patient inclusion and exclusion criteria are similar to those discussed above for the randomized trial, except that participation in any of the above trials is the patient inclusion criterion, not the exclusion criterion, and data for considering a DSM-V diagnosis as ineligible can be obtained from the screening visit in the randomized trial.

[0554] Baseline visit. For patients enrolled in the above randomized trial, the baseline visit will be conducted concurrently with the week 13 visit of that trial. The week 13 assessment identified for the baseline visit in that trial does not need to be repeated. For all patients, the baseline visit will be conducted on the same day (day 1) as the scheduled first dose of the investigational drug. For patients who showed clinically significant abnormal laboratory values ​​at week 12 in the above randomized trial, the values ​​at week 13 will serve as the baseline in this trial. Rollover for such patients must be authorized by the medical monitor and may be delayed.

[0555] Titration period (7 weeks). All patients in this study will undergo dose titration, as patients from the pilot study have had the study drug removed for several months prior to enrollment, and patients from the randomized study have had either the study drug or placebo discontinued for one week. Patients will receive 6 mg of dutetrabenazine with a meal in the evening of day 1.

[0556] Maintenance period (47 weeks). At the end of the infusion period, the patient's initial dose for the maintenance period is established. Dose adjustments (upward or downward) of dutetrabenazine may be made during the maintenance period, but only in increments of 6 mg and no more frequently than every 5 days, if necessary. Dose adjustments should be based on all available information, including patient and caregiver / adult reports of adverse events and tic reduction, clinical evaluations of safety and efficacy by the principal investigator, patient weight and CYP2D6 drug status, and information derived from evaluation scales. During the maintenance period, in-person (in-clinic) trial visits are scheduled at weeks 8, 15, 28, 41, and 54 for safety and efficacy evaluations. At week 54, the patient undergoes the complete evaluation described above in the randomized trial.

[0557] Washout and follow-up. All patients will discontinue the study drug at the visit in week 54 and return one week later (week 55) for safety and tic reduction assessment. Patients will receive a follow-up telephone contact for safety assessment one week after the end of the washout period (two weeks after the last dose of the study drug [week 56]).

[0558] Dosage regimen. The investigational drug will be administered as described above in the randomized trial.

[0559] Trial endpoints. Safety endpoints are as described above in the randomized trial. Efficacy endpoints include the primary and secondary efficacy endpoints described above in the randomized trial, with the goal of reducing the severity of motor and articulation / vocal tics. Examination endpoints are as described above in the randomized trial, from baseline to each visit.

[0560] Expected results: In the above study in patients with Tourette syndrome, administration of dutetrabenazine in tolerable doses of 6–48 mg is expected to reduce overall tic severity, both motor and vocal / articulation tics, impairment, and / or general severity scores; improve quality of life, overall life satisfaction, and / or the patient's overall impression of change, or the clinically general impression of change; and improve (lengthen) tic-free intervals. Safety is expected to be consistent with that observed in previous studies.

[0561] QT prolongation Drug interactions in the treatment of patients with HD and other disorders, including abnormal involuntary movements, can also be a significant concern. Depression is a common comorbidity in HD, and patients are often treated with selective serotonin reuptake inhibitors (SSRIs) such as citalopram and escitalopram, which carry a risk of QT prolongation. Furthermore, due to frequent behavioral abnormalities, several studies have shown that patients with HD are frequently treated with antipsychotics (1 / 4 to 2 / 3 of patients with HD receive antipsychotics). Antipsychotics are known to prolong the QT interval. According to FDA guidelines, QT prolongation is more likely to promote the development of cardiac arrhythmias such as torsades de pointes, which can progress to ventricular fibrillation and be fatal. According to US prescribing information, tetrabenazine should not be used with drugs known to prolong the QT interval.

[0562] Study Design: Considering the known risk of tetrabenazine increasing the QT interval, a TQT trial of deutetrabenazine, including tetrabenazine as the treatment group, was conducted in 48 healthy volunteers. This was a single-center, randomized, double-blind, placebo-controlled, and positive-controlled 6-period crossover trial to evaluate the effects of low-dose (12 mg) and high-dose (24 mg) deutetrabenazine on cardiac repolarization based on placebo-adjusted, time-matched changes in the QTcF interval from baseline. Assay sensitivity was established using 400 mg of moxifloxacin as a positive control.

[0563] The key outcome measure was to determine the effect of a single dose of deutetrabenazine on the QTc interval. A 50 mg dose of tetrabenazine was chosen because it is the maximum dose used in the TQT study for tetrabenazine and is the dose that results in warnings and precautions on the product label. A 24 mg dose of deutetrabenazine was chosen because it provides a similar systemic exposure (AUC) to 50 mg of tetrabenazine but has a lower peak concentration (Cmax).

[0564] Results. For duetetrabenazine, doses of 12 mg and 24 mg induced placebo-adjusted, time-matched maximum increases in QTc of 2.8 ms and 4.5 ms, respectively. For duetetrabenazine, the placebo-adjusted change from baseline in QTcF and the upper bound of the two-sided 90% confidence interval were below the regulatory threshold (5 ms) for both dose levels. In contrast, the maximum time-matched, placebo-adjusted change from baseline in QTcF for tetrabenazine 50 mg was 7.6 ms, which was consistent with the tetrabenazine prescribing information. The results are given in Table 25 below.

[0565] [Table 25]

[0566] In the table above, ΔΔQTcF is defined as the difference between the least-squares mean change from baseline for the active drug and placebo. Dutetrabenazine was compared to dutetrabenazine placebo (administered under fed conditions), and tetrabenazine was compared to tetrabenazine placebo (administered under fasting conditions). Maximum ΔΔQTcF was observed at 8 hours for dutetrabenazine and at 3 hours for tetrabenazine. The upper limit of the 95% one-sided confidence interval is the upper limit of the 90% two-sided confidence interval.

[0567] Conclusion. These results indicate a different pharmacokinetic profile and lower C25 compared to tetrabenazine associated with deutetrabenazine. max However, this supports the fact that it improves the safety profile of dutetrabenazine by reducing the risk of fatal arrhythmias.

[0568] From the above description, those skilled in the art will be able to identify the essential features of the present invention and make various modifications and alterations to adapt it to various uses and conditions without departing from its spirit and scope.

Claims

1. a) The step of discontinuing the administration of the daily dose in which tetrabenazine is present; b) a step of administering the initial total daily dose of deutetrabenazine to a human on the following day; a composition comprising deutetrabenazine for treating tardive dyskinesia by transferring a human subject receiving a daily dose of tetrabenazine from tetrabenazine to deutetrabenazine, The daily dose of tetrabenazine present is 12.5 mg, and the initial total daily dose of duetetrabenazine is 6 mg; The daily dose of tetrabenazine present is 25 mg, and the initial total daily dose of duetetrabenazine is 12 mg; The daily dose of tetrabenazine present is 37.5 mg, and the initial total daily dose of duetetrabenazine is 18 mg; The daily dose of tetrabenazine present is 50 mg, and the initial total daily dose of duetetrabenazine is 24 mg; The daily dose of tetrabenazine present is 62.5 mg, and the initial total daily dose of duetetrabenazine is 30 mg; The daily dose of tetrabenazine present is 75 mg, and the initial total daily dose of duetetrabenazine is 36 mg; The daily dose of tetrabenazine present is 87.5 mg, and the initial total daily dose of duetetrabenazine is 42 mg; or A composition in which the daily amount of tetrabenazine present is 100 mg, and the initial total daily amount of duetetrabenazine is 48 mg.

2. The initial total daily dose of deutetrabenazine is 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg, and the initial total daily dose of deutetrabenazine is administered in two doses. The first dose is 6 mg, and the second dose is 6 mg; The first dose is 9 mg, and the second dose is 9 mg; The first dose is 12 mg, and the second dose is 12 mg; The first dose is 15 mg, and the second dose is 15 mg; The first dose is 18 mg, and the second dose is 18 mg; The first dose is 21 mg, and the second dose is 21 mg; or The composition according to claim 1, wherein the first dose is 24 mg and the second dose is 24 mg.

3. c) After one week, a step of determining the degree of control of tardive dyskinesia achieved using the initial total daily dose of deutetrabenazine and the tolerability of the initial daily dose of deutetrabenazine; and d) A step of increasing the total daily dose of deutetrabenazine in humans by 6 mg / day increments, provided that the degree of control of the tardive dyskinesia is insufficient and the initial total daily dose is tolerable; The composition according to claim 2, further comprising:

4. e) The composition according to claim 3, further comprising the step of repeating steps c) and d) in the human being, provided that after one week the tardive dyskinesia is reduced and the total daily dose of deutetrabenazine is tolerable.

5. The composition according to claim 4, further comprising the step of reducing the daily dose in the human subject by 6 mg / day if the subsequent daily dose is not tolerated.

6. The composition according to claim 4, further comprising repeating step e) until the degree of control of tardive dyskinesia is sufficient and the daily dose of deutetrabenazine becomes tolerable.

7. The initial total daily dose of deutetrabenazine is 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg. c) After one week, a step of determining the degree of control of tardive dyskinesia achieved using the initial total daily dose of deutetrabenazine and the tolerability of the initial total daily dose of deutetrabenazine; and d) A step of increasing the total daily dose of deutetrabenazine in the human subject by 6 mg / day increments, provided that the degree of control of the tardive dyskinesia is insufficient and the initial total daily dose is tolerable; The composition according to claim 1, further comprising:

8. The subsequent daily doses are 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg. e) The composition according to claim 7, further comprising the step of repeating steps c) and d) in a human being, provided that after one week the tardive dyskinesia is reduced and the total daily dose of deutetrabenazine is tolerable.

9. The aforementioned daily dose is 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg. The composition according to claim 8, further comprising repeating step e) until the degree of control of tardive dyskinesia is sufficient and the total daily dose of deutetrabenazine is tolerable.

10. The composition according to claim 9, wherein the total maximum daily dose is 48 mg.

11. The composition according to claim 9, wherein the total maximum daily dose is 36 mg.

12. The composition according to claim 11, wherein the human being simultaneously receives a potent CYP2D6 inhibitor.

13. The composition according to claim 12, wherein the potent CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or ritonavir.

14. The composition according to claim 13, wherein the potent CYP2D6 inhibitor is fluoxetine, paroxetine, or bupropion.

15. The composition according to claim 1, wherein the daily dose of tetrabenazine is 12.5 mg, and the initial total daily dose of duetetrabenazine is 6 mg.

16. The composition according to claim 1, wherein the daily dose of tetrabenazine is 25 mg, and the initial total daily dose of duetetrabenazine is 12 mg.

17. The composition according to claim 16, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 6 mg and the second dose being 6 mg.

18. The composition according to claim 1, wherein the daily dose of tetrabenazine is 37.5 mg, and the initial total daily dose of duetetrabenazine is 18 mg.

19. The composition according to claim 18, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 9 mg and the second dose being 9 mg.

20. The composition according to claim 1, wherein the daily dose of tetrabenazine is 50 mg, and the initial total daily dose of duetetrabenazine is 24 mg.

21. The composition according to claim 20, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 12 mg and the second dose being 12 mg.

22. The composition according to claim 1, wherein the daily dose of tetrabenazine is 62.5 mg, and the initial total daily dose of duetetrabenazine is 30 mg.

23. The composition according to claim 22, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 15 mg and the second dose being 15 mg.

24. The composition according to claim 1, wherein the daily dose of tetrabenazine is 75 mg, and the initial total daily dose of duetetrabenazine is 36 mg.

25. The composition according to claim 24, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 18 mg and the second dose being 18 mg.

26. The composition according to claim 1, wherein the daily dose of tetrabenazine is 87.5 mg, and the initial total daily dose of duetetrabenazine is 42 mg.

27. The composition according to claim 26, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 21 mg and the second dose being 21 mg.

28. The composition according to claim 1, wherein the daily dose of tetrabenazine is 100 mg, and the initial total daily dose of duetetrabenazine is 48 mg.

29. The composition according to claim 28, wherein the initial total daily dose of deutetrabenazine is administered in two doses, the first dose being 24 mg and the second dose being 24 mg.

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