EA044015B1 - DEUTETRABENAZINE FOR THE TREATMENT OF DYSKINESIA IN CEREBRAL PALSY - Google Patents

Description

Cross reference to related applications

This application claims the benefit of U.S. Provisional Applications No. 62/779232, filed December 13, 2018, and No. 62/801450, filed February 5, 2019, both of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

The disclosure relates to methods for treating dyskinesia in cerebral palsy in sick people, including pediatric patients, using deutetrabenazine and its active metabolites.

State of the art

Deutetrabenazine ((rr,ss)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2h-benzo[a]quinolysine-2 -one) is a vesicular monoamine transporter type 2 (vmat2). Biologically active metabolites derived from deutetrabenazine (alpha-dihydrotetrabenazine [α-htbz] and beta-dihydrotetrabenazine [β-htbz]) are potent inhibitors of vmat2 binding with inhibition constant values of 3.8 and 22 nM, respectively. Deutetrabenazine exhibits an increased half-life of its active metabolites compared to tetrabenazine (eg, US Pat. No. 8,524,733).

Deutetrabenazine is approved by the US Food and Drug Administration under the brand name austedo® for the treatment of chorea associated with huntington's disease (hd) and for the treatment of tardive dyskinesia (td) in adults. Pharmaceutical compositions comprising deutetrabenazine are disclosed in US Patent No. 9233959. US Published Application No. 2016/0287574 discloses deutetrabenazine for the treatment of pathological involuntary movement disorders.

Cerebral palsy (DCP) is a non-progressive disorder of brain function that typically occurs in the developing brain of a fetus or infant (age <2 years). CP is the most common and costly form of chronic motor disability in children, with a prevalence of 2 to 4 per 1,000 live births in the United States (US), and the condition is more common in boys than girls. Although there have been no general studies of life expectancy in people with RS, most children with RS live between 30 and 70 years of age, depending on the severity of the condition. In general, a child with mild DCP usually lives longer than a child with mobility and intellectual limitations. There are approximately 764,000 children and adults with CP in the United States, including approximately 500,000 children under age 18. Prematurity is the most common cause of CP, but other causes include stroke, hypoxic ischemic injury, infection, or brain malformations.

Complications of CP may include eye movement disorders, communication problems, difficulty swallowing, poor weight gain, social isolation, hip dysplasia and dislocation, scoliosis, osteopenia and fractures and pain. Various movement disorders are associated with SD, including spasticity, dyskinesia (dystonia, chorea, athetosis, and even ballismus) and ataxia. Many patients with SD have mixed types of movement disorders.

Dyskinesia is believed to result from nonprogressive damage to the basal ganglia of the brain. Dyskinesia in cerebral palsy (DCP) is a hyperkinetic movement disorder characterized by abnormal involuntary movements of dystonic and choreiform types in approximately 6-15% of patients with CP. DCP is a rare disorder, and based on the US prevalence figures for CP reported above, it would be estimated that approximately 30,000 to 75,000 children aged <18 years and 16,000 to 40,000 adults have DCP.

There are currently no approved treatments for DCP, which is a serious condition with an underserved medical need. Current off-label treatments for dystonia and chorea include tetrabenazine, dopaminergic, or gamma-aminobutyric acidergic interventions, but these demonstrate high variability in response. Botulinum neurotoxin A is also used clinically to treat spasticity and dystonia and is considered moderately effective in selected patients, but it does not meet the need for complete treatment. Naxibimol, a non-smokable cannabis derivative, was approved for the treatment of spasticity associated with multiple sclerosis in the United Kingdom in 2010 and is being studied for the treatment of spasticity in MS. Currently, there are very few agents with novel mechanisms of action in the development of movement disorders in SR. Dalfampridine, a small molecule potassium channel blocker thought to restore conduction in central demyelinated axons, is approved for use in multiple sclerosis but has not demonstrated functional improvement in patients with MS.

Thus, there is a need for effective treatments for DCP.

The essence of the invention

The present disclosure relates to methods of treating dyskinesia due to cerebral palsy in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II), or a combination thereof:

ABOUT HE

or a pharmaceutically acceptable salt thereof, wherein each position designated D has a deuterium enrichment of at least about 10%.

The present invention also provides methods for treating dyskinesia associated with cerebral palsy in a human patient, comprising administering to the patient a daily amount of deutetrabenazine from about 6 mg/day to about 48 mg/day in one or two doses, wherein the patient's abnormal involuntary movements associated with dyskinesia in cerebral palsy paralysis are reduced compared to the patient's pathological involuntary movements associated with dyskinesia in cerebral palsy at baseline.

Detailed Description of Illustrative Embodiments

The subject matter of the present invention may be more readily understood by reference to the following detailed description, which forms part of the present disclosure. It should be understood that the present invention is not limited to the specific methods, conditions or parameters described and/or shown herein, and that the terminology used in this description is intended to describe specific embodiments by way of example only and is not intended to limit the claimed invention .

Unless otherwise defined herein, scientific and technical terms used in connection with this application have the meanings commonly understood by those skilled in the art. In addition, unless the context otherwise requires, terms in the singular shall include the plural and terms in the plural shall include the singular.

It should be understood that, as used above and throughout the disclosure, the following terms and abbreviations, unless otherwise noted, have the following meanings.

As used herein, the singular forms a, an, and the include a reference to the plural, and a reference to a specific numeric value includes at least that specific value unless the context clearly indicates otherwise. Thus, for example, a reference to a compound is a reference to one or more such compounds and their equivalents known to those skilled in the art, and so on. As used herein, the term plural means more than one. When a range of values is expressed, another embodiment includes from one specific and/or to another specific value. Likewise, when values are expressed as approximations using the preceding approximately, it is implied that the particular value constitutes another embodiment. All ranges are included and combinable.

As used herein, the terms composition, composition of compounds, compound, drug, pharmacologically active agent, active agent, therapeutic, therapy, treatment, or drug are used interchangeably to mean a compound or compounds or composition of a substance that, when administered to a subject (human or animal) cause the desired pharmacological and/or physiological effect through local and/or systemic action.

As used herein, the terms treatment or therapy (as well as various forms thereof) include preventative (eg, prophylactic), curative, or palliative treatment. As used herein, the term treatment includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease, or disorder. This condition, disease or disorder is classified as DCP.

The term administration means either the direct administration of a compound or composition of the present invention, or the administration of a prodrug, derivative or analog that will form an equivalent amount of the active compound or substance in the body.

The terms subject, individual and patient are used interchangeably herein and refer to a person receiving treatment, including prophylactic treatment, with a pharmaceutical composition according to the present invention.

Pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are medically suitable for contact with human tissue without undue toxicity, irritation, allergic reaction or other complication problems commensurate with a reasonable benefit/risk ratio.

Within the scope of the present invention, the disclosed compounds can be obtained in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to derivatives of the described compounds in which the parent compound is modified by producing their acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids with basic moieties such as amines; alkaline or organic salts of acid residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamonic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, etc. These pharmaceutically acceptable salts are prepared by methods known in the art, for example, by dissolving the free amine bases with excess acid in an aqueous alcohol or neutralizing the free carboxylic acid with an alkali metal base, such as a hydroxide, or an amine.

The terms item and score are used interchangeably here and refer to the measure of a specific rating scale.

In some aspects, the present disclosure provides methods for treating DCP in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II), or a combination thereof:

or a pharmaceutically acceptable salt thereof, wherein each position designated D has a deuterium enrichment of at least about 10%.

In some embodiments, the method includes administering a compound of formula (I). The compound of formula (I), having the chemical name 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2methylpropyl)-2H-benzo[a]quinolysine-2- it has two stereogenic carbon atoms, which give four stereoisomers of the compound of formula (I): IA, IB, IC, ID:

A racemic mixture of stereoisomers (R,R) and (S,S) (i.e. a mixture of IA and IB) is called deutetrabenazine. In some embodiments, the method includes administering a racemic mixture of (R,R) and (S,S) stereoisomers (ie, a mixture of IA and IB) called deutetrabenazine.

As used herein, a compound of formula (I) refers to compounds of formulas IA, IB, IC or ID, as well as mixtures of compounds of formulas IA, IB, IC or ID in any proportion.

In some embodiments, a compound of formula (I) refers to deyetrabenazine.

In some embodiments, the method includes administering a compound of formula (II). The compound of formula (II), having the chemical name 3-isobutyl-9,10-bis(methoxy-d3)-1,3,4,6,7,11bhexahydro-2H-pyrido[2,1-a] isoquinolin-2-ol, has three stereogenic carbon atoms, which give eight stereoisomers of the compound of formula (II): IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH:

In this context, a compound of formula (II) refers to compounds of formulas IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, as well as mixtures of compounds of formula IIA, IIB, IIC, IID, IIE, IIF, IIG or IIH in any proportion.

Deuteratrabenazine is metabolically reduced to deuterated alpha-dihydrotetrabenazine (α-HTBZ) (i.e. IIA and IIF) and deuterated beta-dihydrotetrabenazine (β-HTBZ) (i.e. IIB and IIE).

In some aspects, the method of the disclosure includes administering a compound of formula (I) or formula (II) or a combination thereof, or a pharmaceutically acceptable salt thereof, wherein each position represented by D has a deuterium enrichment of at least about 10%. In this context, deuterium enrichment refers to the percentage of hydrogen atoms at a given position that are an isotope of deuterium (i.e. ^2H ) rather than 1H and/or ^3H isotopes. For example, 10% deuterium enrichment means that 10% of the atoms hydrogen at this position are deuterium, and 90% of the hydrogen atoms at this position are isotopes 1H and/or ^3H . Methods for determining the hydrogen isotope content are known to those skilled in the art and include mass spectroscopy and NMR.

In some embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 10%.

In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 20%.

In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 50%.

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In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 70%.

In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 80%.

In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 90%.

In other embodiments of the methods of the disclosure, each position in formula (I) or formula (II) represented by D has a deuterium enrichment of at least about 98%.

In some aspects, in the methods of the disclosure, administration of a compound of formula (I) results in a significant increase in the maximum tolerated dose, a decrease in toxicity, an increase in half-life (t _1/2 ) or a decrease in the maximum plasma concentration (C _max ) of the minimum effective dose (MED) or combinations thereof compared with an equally effective dose of the corresponding non-deuterated compound.

As used herein, a corresponding non-deuterated compound of formula (I) refers to a compound having the structure

The corresponding non-deuterated compound of formula (II) refers to a compound having the structure

As used herein, with respect to a compound of formula (I), an equally effective dose of the corresponding non-deuterated compound refers to the dose of the corresponding non-deuterated compound that produces the same improvement in the dyskinesia of a cerebral palsy patient as a specific dose of the compound of formula (I). With respect to a compound of formula (II), an equally effective dose of the corresponding non-deuterated compound refers to the dose of the corresponding non-deuterated compound that produces the same improvement in the dyskinesia of a cerebral palsy patient as a specific dose of the compound of formula (II).

In some aspects, administration of a compound of formula (I), (II), or a combination thereof results in a substantially increased maximum tolerated dose compared to administration of an equally effective dose of the corresponding non-deuterated compound.

In other aspects, administration of a compound of formula (I), (II), or a combination thereof results in lower toxicity compared to administration of an equally effective dose of the corresponding non-deuterated compound.

In other aspects, administration of a compound of formula (I), (II), or a combination thereof results in an increase in the half-life (t _1/2 ) of the compound of formula (I) or (II) compared to an equally effective dose of the corresponding non-deuterated compound.

In other aspects, administration of a compound of formula (I), (II), or a combination thereof results in a decrease in C _max MED compared to administration of an equally effective dose of the corresponding non-deuterated compound.

In some aspects, the methods of the present disclosure are directed to treating dyskinesia due to cerebral palsy (DCP) in a human patient. Dyskinesia in cerebral palsy refers to a hyperkinetic movement disorder characterized by pathological involuntary movements of dystonic and/or choreiform types. Dystonic pathological involuntary movements occur as a result of involuntary muscle spasms. Choreiform types of abnormal involuntary movements include chorea, athetosis, and tremor/ballismus.

In some embodiments of the methods of the disclosure, the abnormal involuntary movements associated with DCP are of the dystonic type.

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In other embodiments of the methods of disclosure, the abnormal involuntary movements associated with DCP are of the choreiform type.

In other embodiments of the methods of disclosure, the abnormal involuntary movements associated with DCP are dystonic type and choreiform type.

In yet other embodiments of the methods of disclosure, the abnormal involuntary movements associated with DCP are of the dystonic type or the choreiform type.

In some aspects, the disclosure methods are applied to a sick person. In some embodiments of the methods of the disclosure, the sick person is a pediatric patient. As used herein, the term pediatric patient refers to a patient 18 years of age or younger. In some embodiments of the methods of the disclosure, the sick person is an adult patient. As used herein, the term adult patient refers to a patient over 18 years of age.

In some embodiments of the methods of the disclosure, the age of the patient is between 6 and 18 years.

In other embodiments of the methods of the disclosure, the age of the patient is between 6 and <12 years.

In other embodiments of the methods of the disclosure, the age of the patient is between 12 and 18 years.

In still other embodiments of the methods of the disclosure, the age of the patient is less than 6 years.

In some aspects of the methods of the disclosure, the age of the patient is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or about 18 years. In some aspects of the methods of the disclosure, the age of the patient is about 1, 2, 3, 4, about 5 years. In some aspects of the methods of the disclosure, the age of the patient is about 6, 7, 8, 9, 10, or about 11 years. In some aspects of the disclosure methods, the age of the patient is about 12, 13, 14, 15, 16, 17, or about 18 years.

In some aspects, the methods of the disclosure further administer an additional therapeutic agent to the patient. As used herein, an additional therapeutic agent refers to an agent other than a compound of formula (I) and/or formula (II) that is administered to treat one aspect of the patient's cerebral palsy, such as, for example, eye movement abnormalities, communication problems , difficulty swallowing, poor weight gain, social isolation, hip dysplasia and dislocation, scoliosis, osteopenia and fractures, pain and movement disorders. Examples of additional therapeutic agents include anticholinergics (eg, benztropine mesylate, carbidopa-levodopa, glycopyrrolate, procyclidine hydrochloride, and trihexyphenidyl hydrochloride), anticonvulsants (eg, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide), antidepressants (eg, citalopram, uscitalopram, fluoxetine, paroxetine and sertraline), antispastic agents (eg, botulinum toxin, diazepam, dantrolene, cyclobenzadrine, intrathecal baclofen and tizanidine) and anti-inflammatory drugs (eg, aspirin, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and steroid drugs). In some embodiments of the method of administration, the additional therapeutic agent is administered simultaneously with, before, or after administration of a compound of formula (I), formula (II), or a combination thereof.

In some aspects, the disclosure relates to methods of treating dyskinesia due to cerebral palsy in a human patient, comprising administering to the patient a daily amount of a compound of formula (I) from about 6 mg/day to about 48 mg/day in one or two doses.

In some aspects of the methods of the disclosure, the patient is administered a daily amount of deutetrabenazine from about 6 mg/day to about 48 mg/day in one or two doses.

As used herein, the terms daily amount or daily dosage may be used interchangeably and refer to the dose to be administered per day that is optimal, as determined, for example, by the attending physician through dose titration or other method. The period of time immediately before starting deyetrabenazine therapy is called baseline. The patient's condition immediately before starting deyetrabenazine therapy can be considered the patient's baseline condition. The daily amount or daily dose is administered to the patient in one or two doses, further described herein below.

In some embodiments, the daily amount of deutetrabenazine is from 6 mg/day to 48 mg/day. In some embodiments, the daily amount of deutetrabenazine is 6 mg/day.

In some variants, 12 mg/day.

In some embodiments, 18 mg/day.

In some variants, 24 mg/day.

implementation daily implementation daily implementation the daily amount of deutetrabenazine is the amount of deutetrabenazine is the amount of deutetrabenazine is

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In some embodiments, the daily amount of deutetrabenazine is 30 mg/day.

In some embodiments, the daily amount of deutetrabenazine is 36 mg/day.

In some embodiments, the daily amount of deutetrabenazine is 42 mg/day.

In some embodiments, the daily amount of deutetrabenazine is 48 mg/day.

In some aspects of the methods of the disclosure, the daily amount may be administered in one or two doses. In some embodiments, the daily amount is administered in a single dose. In other embodiments, the daily amount is administered in two doses.

When the daily dose is administered in two doses, the two doses may be equal or different. In some embodiments, each of the two doses is an equal amount.

When the daily amount is administered in two doses, the two doses may be equal or different in amount. In some embodiments, both two daily doses are equal doses.

When the daily amount is administered in two doses, the administration of the doses is separated by an intervening period of time. In some embodiments, the second dose is administered approximately 8-10 hours after the first dose. In other embodiments, the second dose is administered approximately 8 hours after the first dose. In other embodiments, the second dose is administered approximately 10 hours after the first dose.

In some embodiments, a titration regimen is used to determine the initial daily dose of a compound of formula (I). In some embodiments, a titration regimen is used to determine the initial daily dose of a compound of formula (II) or a combination of formula (I) and formula (II). In some embodiments, the initial daily dose is different from the maintenance daily dose.

In some embodiments, administration includes:

a) administering to the subject an initial daily amount of deutetrabenazine of at least about 6 mg per day;

b) determining, after approximately one week, the degree of control of pathological involuntary movement associated with DCP achieved with the initial daily amount and the tolerance of the initial daily amount;

c) increase the daily amount of deutetrabenazine by 6 mg/day or more to a subsequent daily amount if the degree of control of abnormal involuntary movements associated with DCP is inadequate and the initial daily amount is tolerated;

d) optionally repeating steps b) and c) until the degree of control of abnormal involuntary movement associated with DCP is adequate and the daily amount of deutetrabenazine is tolerated; And

e) if any subsequent amount is not tolerated, reduce the daily amount by 6 mg/day or more to the next daily amount.

In some aspects, the treatment results in maintenance of the patient's abnormal involuntary movements associated with DCP, compared to the patient's abnormal involuntary movements associated with DCP at baseline. As used herein, maintaining the patient's abnormal movements means that the patient's abnormal movements associated with DCP do not change from baseline. Thus, the patient's pathological involuntary movements associated with DCP remain stabilized; they do not improve, but do not worsen. This treatment represents clinical benefit for patients who have a history of worsening abnormal involuntary movements associated with DCP.

In some aspects of the methods of the disclosure, treatment with a compound of formula (I) and/or a compound of formula (II) results in a reduction in the patient's DCP-related abnormal movements compared to the DCP-related abnormal movements of the patient at baseline. In some aspects of the methods herein, treatment with a compound of formula (I) results in a reduction in the patient's DCP-related abnormal movements compared to the patient's DCP-related abnormal movements at baseline. In some aspects of the methods herein, treatment with deutetrabenazine results in a reduction in the patient's abnormal involuntary movements associated with DCP compared to the patient's abnormal involuntary movements associated with DCP at baseline.

In some aspects of the methods of the disclosure, treatment with a compound of formula (II) results in a reduction in the patient's DCP-related abnormal movements compared to the patient's DCP-associated abnormal movements at baseline. In some aspects of the methods herein, treatment with deuterated α-HTBZ or deuterated β-HTBZ results in a reduction in patient abnormal movements associated with DCP compared to abnormal patient movements associated with DCP at baseline.

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In some aspects, the patient's abnormal involuntary movements associated with DCP are measured using a clinical assessment tool, such as, for example, at least one of the rating scales: a) MD-CRS Part II; b) MD-CRS Part I; c) CaGI-I and d) CGI-I. One such clinical tool is the Movement Disorder Rating Scale for Children (MD CRS) index. See, for example, Battini R, et al., Responsiveness of the MD-Childhood Rating Scale in dyskinetic cerebral palsy patients undergoing anticholinergic treatment. Eur J Paediatr Neurol 2014; 18 (6): 698-703; Battini R, et al., Movement Disorder-Childhood Rating Scale: reliability and validity. Pediatr Neurol 2008; 39 (4): 259-65, which are incorporated herein by reference in their entirety.

The MD-CRS consists of 2 parts, Part I and Part II, where a higher score indicates worsening condition.

Part I of the MD-CRS assesses the impact of DCP on a patient's activities and provides a global movement disorder score for motor function (7 items), oral/verbal function (3 items), self-care (3 items), and attention/vigilance (2 items). scale from 0 (present) to 4 (absent). The MD-CRS Part I total score (0 to 60) can be normalized to a range of 0 to 1 called the I index.

The MD CRS Part II is a specific motor assessment of the severity of a movement disorder, in this case involuntary movements associated with DCP. Part II of the MD-CRS rates the severity of the movement disorder on a scale of 0 to 4 in each of 7 body regions in which dyskinesia is observed in patients with SD. Therefore, the maximum possible MD-CRS Part II total score is 28. The MD-CRS Part II total score (0 to 28) can be normalized to a range of 0 to 1, called index II. In the MD-CRS Part II, a score of 0 refers to the absence of a movement disorder, and a score of 4 refers to a situation where the movement disorder is present during all tasks for the domain of interest and/or includes 3 or more from other domains, making completion impossible. 7 Body Regions Assessed by MD-CRS Part II: (i) Eye and Periorbital Region, (ii) Face, (iii) Tongue and Perioral Region, (iv) Neck, (v) Torso, (vi) Upper Extremity and (vii) lower limb. The MD-CRS does not differentiate between dyskinesia in dystonic or choreiform cerebral palsy, and the worst dyskinesia in any of the regions observed during the assessment session is taken as the score for each body region affected.

Another assessment tool is the Caregiver Global Impression of Improvement (CaGI-I) scale. The CaGI-I is a one-item questionnaire assessing caregiver impressions of improvement in dyskinesia symptoms in cerebral palsy following initiation of therapy. The scale is a caregiver-reported outcome that aims to assess all aspects of the patient's health and measure overall improvement in dyskinesia symptoms. Caregiver ratings are 1=very much improved (since start of treatment); 2=significant improvement; 3=minimal improvement; 4=no change from baseline (symptoms have not changed significantly); 5=minimally worse; 6=much worse; or 7=very much worse (since the start of treatment).

Another assessment tool is the Clinical Global Impression of Improvement (CGI-I), a physician-reported outcome that uses a 7-point scale that allows the physician to compare the patient's condition since the start of treatment with the baseline condition as follows: 1=very much improvement since start of treatment (almost better; good level of functioning; minimal symptoms; represents a very significant change); 2=major improvement (noticeably better with significant improvement in symptoms; increased level of functioning but some symptoms remaining); 3=minimal improvement (slightly better with little or no clinically significant improvement in symptoms; represents very little change in underlying clinical status, level of treatment, or functionality); 4=no change from baseline (symptoms essentially unchanged); 5=minimally worse (slightly worse, but may not be clinically significant; may represent very little change in underlying clinical status or functionality); 6=much worse (clinically significant increase in symptoms and decrease in functionality); 7=very severe deterioration since the start of treatment (severe worsening of symptoms and loss of function). See, for example, Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry (Edgmont) 2007; 4 (7): 28-37, which is incorporated herein by reference in its entirety.

Another assessment tool is the Clinical Global Impression of Severity (CGI-S), which uses a 7-point Likert scale to rate the severity of dyskinesia as follows (with anchor points to select the most appropriate level of DCP-induced severity): 1=normal (not at all sick, no symptoms of the disorder for 7 days); 2=borderline (undetected or suspected pathology); 3=mild (well-defined symptoms with minimal distress or difficulty in social and/or occupational functioning, if any); 4=moderate (obvious symptoms causing noticeable but moderate functional impairment or distress; level of symptoms may require medication); 5=severe (intrusive symptoms that clearly impair social/occupational function or cause obsessive levels of distress); 6=severe (disruptive symptoms, behavior, and function are often symptom-dependent and may require assistance from others); 7=extreme (symptoms severely interfere with many vital functions; may require hospitalization).

Another assessment tool is the Pediatric Disability Assessment Computer Adapted Test (PEDI-CAT), which is a clinical assessment for children and youth. The PEDI CAT includes an extensive bank of 276 functional activities acquired during infancy, childhood, and adolescence. See, for example, the work of Dumas HM, Fragala-Pinkham MA. Concurrent Validity and Reliability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test Mobility Domain. Pediatric Physical Therapy 2012; 24: 171-76, which is incorporated herein by reference in its entirety.

Another assessment tool is the Pediatric Quality of Life Inventory (PedsQL), which is a health-related quality of life instrument that consists of a well-validated general core score and some condition- and disease-specific modules (work by Varni, J. W. et al. The PedsQL ™ in pediatric cerebral palsy: Reliability, validity, and sensitivity of the Generic Core Scales and Cerebral Palsy Module. Developmental Medicine and Child Neurology 2006;48:442-49, which is incorporated herein by reference in its entirety). The 35-item PedsQL 3.0 CP module includes 7 scales: (1) daily activities (9 items); (2) school activities (4 subjects); (3) movement and balance (5 items); (4) pain and pain (4 items); (5) fatigue (4 items); (6) food (5 items); and (7) speech and communication (4 items). The instructions ask how much of a problem each item was in the last 1 month. A 5-point response scale is used in the child self-report and parent proxy report as follows: 0=never been a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem.

Another assessment tool is the Patient Global Impression of Improvement (PGI-I), which is a single-item questionnaire assessing the patient's impression of improvement in dyskinesia symptoms after initiation of the described therapy. The PGI-I is a patient-reported outcome that aims to assess all aspects of the patient's health and determine whether there has been an overall improvement in dyskinesia symptoms. The patient must select 1 answer from the visual response options (emoticons) that most accurately describes his/her health status and general condition: 1=significantly improved (since the start of treatment); 2=somewhat improved; 3=no change; 4=somewhat worse; 5=much worse (since treatment started).

Another assessment tool is the 15-item Unified Huntington's Disease Rating Total Motor Scale (UHDRS-TMS), which assesses eye movements, speech, alternating hand movements, dystonia, chorea, and gait. The UHDRS-TMS is calculated as the sum of 31 motor scores, each with a range of 0 to 4 points. The overall minimum score is 0 (none) and the maximum is 124 (worst). The Unified Huntington's Disease Rating Scale for Total Maximal Chorea (UHDRS-TMC) is part of the UHDRS-TMS score and assesses the severity of chorea in the face, mouth, trunk, and 4 limbs. The minimum score is 0 (absent), the maximum score is 28 (checked/extended). The Unified Huntington's Disease Rating Scale for Total Maximum Dystonia (UHDRS-TMD) is part of the UHDRS-TMS score and assesses the severity of trunk and 4-limb dystonia. The minimum score is 0 (absent) and the maximum score is 20 (checked/extended). See, for example, the work of the Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord 1996; 11(2):136-42, which is incorporated herein by reference in its entirety.

Another assessment tool is the Canadian Labor Productivity Measure (COPM). The SORM is designed to assess patient outcomes regarding self-care, productivity, and leisure activities. Using a semi-structured interview, SORM is a 5-step process that measures individual, patient-identified problem areas in daily activities. Two ratings were received: for effectiveness and job satisfaction. Law M, et al. The Canadian occupational performance measure: an outcome measure for occupational therapy. Can J Occup Ther 1990 Apr; 57 (2): 82-7, which is incorporated herein by reference in its entirety.

In some aspects, treatment safety is measured by the Columbia Suicidality Severity Rating Scale (SSRS), which measures the frequency and severity of suicidal thoughts or behavior. See, for example, Posner K, et al. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings from Three Multisite Studies With Adolescents and Adults. American Journal of Psychiatry 2011; 168 (12): 1266-77, which is incorporated herein by reference in its entirety.

In some embodiments of the methods for disclosing the patient's abnormal involuntary movements associated with the DCP are measured by at least one clinical assessment instrument. For example, in some aspects of the methods for disclosing the patient's abnormal involuntary movements associated with DCP are measured by at least one instrument from the Movement Disorder Rating Scale for Children (MD CRS) index;

- 9 044015 Caregiver Global Impression of Health Improvement (CaGI-I) scale;

Clinical Global Impression of Improvement (CGI-I);

Clinical Global Impression of Severity (CGI-S);

computer-adapted Pediatric Disability Inventory Test (PEDI-CAT);

Pediatric Quality of Life Inventory (PedsQL);

Patient Global Impression of Improvement (PGI-I);

Unified Huntington's Disease Rating Scale - Total Motor Rating Scale (UHDRS-TMS);

Columbia Suicidality Severity Scale (SSRS) Canadian Work Productivity Measure (COPM).

In some embodiments of the methods for disclosing the patient's abnormal involuntary movements associated with DCP are measured by at least one of a) MD-CRS Part II; b) MD-CRS Part I; c) CaGI-I; and d) CGI-I.

In some embodiments, a reduction in abnormal involuntary movements associated with DCP is demonstrated by at least one of the following:

a) decrease in MD-CRS Part II total score from baseline occurs by week 15;

b) decrease in MD-CRS Part I total score from baseline occurs by week 15;

c) a decrease in CaGI-I from baseline occurs by week 15; And

d) the CGI-I score decreases from baseline by week 15.

In some embodiments of the disclosure methods, the patient's abnormal involuntary movements associated with DCP are measured by the change from baseline to week 15 in the MD-CRS Part II score.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >8 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >10 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >12 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >14 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >16 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient at baseline has a total score of >18 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient's total score at baseline is >20 on the MD-CRS Part II items.

In some embodiments of the disclosure methods, the patient's abnormal involuntary movements associated with DCP are measured by the change from baseline to week 15 in the MD-CRS Part I score.

In some embodiments of the disclosure methods, the patient's MD-CRS Part I total score is reduced by approximately 1 to 8 points from baseline. In some embodiments of the disclosure methods, the patient's overall MD-CRS Part I score is reduced by approximately 2 to 4 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 1 point from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 2 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 3 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 4 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 5 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 6 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 7 points from baseline. In some embodiments, the patient's MD-CRS Part I total score is reduced by at least 8 points from baseline. In some embodiments of the methods of the disclosure, a reduction in the MD-CRS Part I total score disclosed herein is observed 15 weeks after the start of treatment. In some embodiments of the methods of the disclosure, the reduction in MD-CRS Part I total score disclosed herein is observed for at least 15 weeks from the start of treatment.

In some embodiments of methods for disclosing pathological involuntary

- 10 044015 patient movements are measured by change from baseline to week 15 on a rating scale

CaGI-I.

In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by approximately 0.2 to 0.8 points compared to baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by approximately 0.5 to 0.7 points compared to baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.2 points from baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.3 points from baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.4 points from baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.5 points from baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.6 points from baseline. In some embodiments of the methods of the disclosure, the patient's CaGI-I score is reduced by at least 0.7 points from baseline. In some embodiments of the methods of the disclosure, the reduction in CaGI-I score disclosed herein is observed after 15 weeks of treatment. In some embodiments of the methods of the disclosure, the reduction in CaGI-I disclosed herein is observed for at least 15 weeks from the start of treatment.

In some embodiments of the disclosure methods, the patient's abnormal involuntary movements are measured by the change from baseline to week 15 on the CGI-I rating scale.

In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by approximately 0.2 to 0.8 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by approximately 0.5 to 0.7 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.2 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.3 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.4 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.5 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.6 points from baseline. In some embodiments of the methods of the disclosure, the patient's CGI-I score is reduced by at least 0.7 points from baseline. In some embodiments of the methods of the disclosure, the reduction in CGI-I score disclosed herein is observed 15 weeks after the start of treatment. In some embodiments of the methods of the disclosure, the reduction in CGI-I score disclosed herein is observed for at least 15 weeks from the start of treatment.

In some aspects of the disclosure methods, the severity of the patient's abnormal involuntary movements associated with the DCP is reduced compared to the severity of the patient's abnormal involuntary movements at baseline.

In some aspects, reduction in the severity of the patient's abnormal involuntary movements associated with DCP is measured using the MD-CRS Part II.

In some embodiments of the disclosure methods, the patient's overall MD-CRS Part II score is reduced by approximately 0.5 to 10 points from baseline. In some embodiments of the disclosure methods, the patient's overall MD-CRS Part II score is reduced by approximately 0.5 to 4 points from baseline. In some embodiments, the patient's MD-CRS Part II total score is reduced by at least 0.5 points compared to the patient's MD-CRS Part II total score at baseline. In some embodiments, the patient's MD-CRS Part II total score is reduced by at least 1 point compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 2 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 3 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MDCRS Part II total score is reduced by at least 4 points compared to the patient's MDCRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 5 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 6 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 7 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 8 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 9 points compared to the patient's MD-CRS Part II total score at baseline. In other embodiments, the patient's MD-CRS Part II total score is reduced by at least 10 points compared to the patient's MD-CRS Part II total score at baseline. In some embodiments of the methods of the disclosure, a reduction in the MDCRS Part II total score disclosed herein is observed 15 weeks after the start of treatment. In some embodiments of the methods of the disclosure, the reduction in MD-CRS Part II total score disclosed herein is observed for at least 15 weeks from the start of treatment.

In some aspects of the methods of the disclosure, the patient's motor function is improved compared to the patient's motor function at baseline following administration of deutetrabenazine. In some embodiments, improvement in the patient's motor function is demonstrated in one or more of seven body regions assessed using MD-CRS Part II: (i) eye and periorbital region, (ii) face, (iii) tongue and periorbital region, ( iv) neck, (v) torso, (vi) upper limb and (vii) lower limb, or combinations thereof.

In some embodiments, the patient's ocular and periorbital motor function improves after deutetrabenazine administration compared to the patient's motor function at baseline. In some embodiments, the patient's ocular and periorbital motor function after administration of deutetrabenazine is improved compared to the patient's motor function at baseline, as demonstrated by a decrease in the ocular and periorbital score on the MD-CRS Part II compared to the baseline score. .

In some embodiments, the patient's facial motor function improves after administration of deutetrabenazine compared to the patient's facial motor function at baseline. In some embodiments, the patient's facial motor function after administration of deutetrabenazine improves compared to the patient's motor function at baseline, as demonstrated by a decrease in the MD-CRS Part II facial score compared to the baseline score.

In some embodiments, the patient's tongue and perioral motor function improves after deutetrabenazine administration compared to the patient's motor function at baseline. In some embodiments, the patient's tongue and perioral motor function after administration of deutetrabenazine is improved compared to the patient's motor function at baseline, as demonstrated by a decrease in the tongue and perioral area score on the MD-CRS Part II compared to the baseline score. .

In some embodiments, the patient's neck motor function improves after administration of deutetrabenazine compared to the patient's neck motor function at baseline. In some embodiments, the patient's neck motor function improves following administration of deutetrabenazine compared to the patient's motor function at baseline, as demonstrated by a decrease in the MD-CRS Part II neck score compared to the baseline score.

In some embodiments, the patient's torso motor function improves after administration of deutetrabenazine compared to the patient's motor function at baseline. In some embodiments, the patient's trunk motor function after administration of deutetrabenazine improves compared to the patient's motor function at baseline, as demonstrated by a decrease in the trunk score on the MD-CRS Part II compared to the score at baseline.

In some embodiments, the patient's torso motor function improves after administration of deutetrabenazine compared to the patient's motor function at baseline. In some embodiments, the patient's upper extremity motor function improves following administration of deutetrabenazine compared to the patient's motor function at baseline, as demonstrated by a decrease in the upper extremity score on the MD-CRS Part II compared to the baseline score.

In some embodiments, the patient's lower extremity motor function improves following administration of deutetrabenazine compared to the patient's motor function at baseline. In some embodiments, the patient's lower extremity motor function after administration of deutetrabenazine improves compared to the patient's motor function at baseline, as demonstrated by a decrease in the MD-CRS Part II lower extremity score compared to the baseline score.

In some aspects of the methods of the present invention, the patient's oral/verbal function after administration of deutetrabenazine is improved compared to the patient's oral/verbal function at baseline. In some embodiments, a patient's oral/verbal function improves following administration of deutetrabenazine compared to the patient's oral/verbal function at baseline, as demonstrated by a decrease in MD-CRS oral/verbal function scores.

- 12 044015 Part I. In some embodiments, the patient's oral/verbal MD-CRS Part I score is reduced by 0.5 points or more from baseline. In some embodiments, the patient's oral/verbal MD-CRS Part I score is reduced by 1 point or more from baseline. In some embodiments, the patient's oral/verbal MD-CRS Part I score is reduced by 2 points or more from baseline. In some embodiments, the patient's oral/verbal MD-CRS Part I score decreases by 3 points or more from baseline. In some embodiments, the patient's oral/verbal MD-CRS Part I score is reduced by 4 points from baseline.

In some aspects of the methods of the disclosure, the patient's self-care function after administration of deutetrabenazine is improved compared to the patient's self-care function at baseline. In some embodiments, the patient's self-care function after administration of deutetrabenazine is improved compared to the patient's self-care function at baseline, as demonstrated by a decrease in the MD-CRS Part I self-care score. The MD-CRS Part I self-care score decreases by 0.5 points or more from baseline. In some embodiments, the patient's MD-CRS Part I self-care score is reduced by 1 point or more from baseline. In some embodiments, the patient's MD-CRS Part I self-care score is reduced by 2 points or more from baseline. In some embodiments, the patient's MDCRS Part I self-care score decreases by 3 points or more from baseline. In some embodiments, the patient's MD-CRS Part I self-care score is reduced by 4 points from baseline.

In some aspects of the methods of the present disclosure, the patient's attention/vigilance after administration of deutetrabenazine is improved compared to the patient's attention/vigilance at baseline. In some embodiments, the patient's attention/vigilance after administration of deutetrabenazine improves compared to the patient's attention/vigilance at baseline, as demonstrated by a decrease in the MD-CRS Part I Attention/Vigilance score. In some embodiments, the attention/vigilance score on the MD-CRS Part I is reduced by 0.5 points or more from baseline. In some embodiments, the patient's MD-CRS Part I attention/vigilance score decreases by 1 point or more from baseline. In some embodiments, the patient's MD-CRS Part I attention/vigilance score decreases by 2 points or more from baseline. In some embodiments, the patient's MD-CRS Part I attention/vigilance score decreases by 3 points or more from baseline. In some embodiments, the patient's MD-CRS Part I attention/vigilance score is reduced by 4 points from baseline.

In some aspects of the disclosure methods, the patient's abnormal involuntary movements are significantly or very improved compared to baseline. In some embodiments, improvement in the patient's abnormal involuntary movements is demonstrated by a score of 1 or 2 on the Caregiver Global Impression of Improvement (CaGI-I) scale or a score of 1 or 2 on the Clinical Global Impression of Improvement (CGI-I) scale.

In some embodiments of the disclosure methods, the patient's abnormal involuntary movements have significantly improved from baseline, as demonstrated by a CaGI-I score of 2.

In other embodiments of the disclosure methods, the patient's abnormal involuntary movements have significantly improved from baseline, as demonstrated by a CGI-I score of 2.

In some embodiments of the disclosure methods, the patient's abnormal involuntary movements have significantly improved from baseline, as demonstrated by a CaGI-I score of 1.

In other embodiments of the disclosure methods, the patient's abnormal involuntary movements have significantly improved from baseline, as demonstrated by a CGI-I score of 1.

In some aspects of the disclosure modalities, the patient has a Clinical Global Impression of Severity (CGI-S) score of 4 or higher at baseline. The CGI-S measures the severity of dyskinesia using a 7-point scale: 1=normal (not painful at all, no symptoms of the disorder after 7 days); 2=borderline (minor or suspected pathology); 3=mild (well-defined symptoms with minimal distress or difficulty in social and/or occupational functioning, if any); 4=moderate (obvious symptoms causing noticeable but moderate functional impairment or distress; level of symptoms may require medication); 5=severe (intrusive symptoms that clearly impair social/occupational function or cause intrusive levels of distress); 6=severe (disruptive symptoms, behavior, and function are often symptom-dependent and may require assistance from others); 7=extreme (symptoms severely interfere with many vital functions; may require hospitalization).

- 13 044015

In some aspects of the disclosure methods, the patient's abnormal involuntary movements associated with DCP are reduced by at least 20% compared to baseline. In some embodiments, the percentage reduction is equivalent to the percentage change in score on one of the clinical assessment tools described herein.

In some aspects, patients to whom the methods of the present disclosure are applied weigh at least 12 kg at baseline. In some aspects, the dose of a compound (eg, Formula (I) or Formula (II)) administered to a patient depends on the patient's weight and whether the patient has a CYP2D6 disorder. As used herein, CYP2D6 impairment means that the patient is administered a strong CYP2D6 inhibitor concomitantly with deutetrabenazine, or that the patient is a poor metabolizer of CYP2D6. Examples of strong CYP2D6 inhibitors include bupropion, fluoxetine, and paroxetine.

In some embodiments of the methods of the disclosure, the patient weighs between 12 kg and <17 kg, such as 12, 13, 14, 15, or about 16 kg, and the patient is administered a daily amount of deutetrabenazine of less than or equal to about 24 mg, unless the patient has a CYP2D6 disorder ; or the patient is administered a daily amount of deutetrabenazine less than or equal to approximately 12 mg if the patient has a CYP2D6 disorder.

In some embodiments of the methods of the disclosure, the patient weighs between 17 kg and <30 kg, such as 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or about 29 kg, and the patient is administered a daily amount of deutetrabenazine less than or equal to approximately 30 mg, unless the patient has a CYP2D6 disorder; or the patient is administered a daily amount of deutetrabenazine less than or equal to approximately 18 mg if the patient has a CYP2D6 disorder.

In some embodiments of the methods of the disclosure, the patient weighs between 30 kg and <40 kg, such as 30, 31, 32, 33, 34, 35, 36, 37, 38, or about 39 kg, and the patient is administered a daily amount of deutetrabenazine that is less than or equal to equal to approximately 42 mg if the patient does not have a CYP2D6 disorder; or the patient is administered a daily amount of deutetrabenazine less than or equal to approximately 24 mg if the patient has a CYP2D6 disorder.

In some embodiments of the disclosure methods, the patient weighs >40 kg, for example, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125 , 130, 135, 140, 145, or about 150 kg, and the patient is administered a daily amount of deutetrabenazine less than or equal to about 48 mg, unless the patient has a CYP2D6 disorder; or the patient is administered a daily amount of deutetrabenazine less than or equal to approximately 36 mg if the patient has a CYP2D6 disorder.

Specific embodiments of the present disclosure include the following.

1) A method of treating dyskinesia in cerebral palsy in a sick person, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II) or a combination thereof:

or a pharmaceutically acceptable salt thereof, wherein each position represented by D has a deuterium enrichment of at least about 10%.

2) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 20%.

3) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 50%.

4) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 70%.

5) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 80%.

6) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 90%.

7) The method of Embodiment 1, wherein each position represented by D has a deuterium enrichment of at least about 98%.

8) The method according to any one of embodiments 1 to 7, wherein the compound is a compound having formula (I) or a pharmaceutically acceptable salt thereof.

9) The method of embodiment 8, wherein the compound of formula (I) is deutetrabenazine.

- 14 044015

10) The method as in any one of embodiments 1 to 7, wherein the compound is a compound having formula (II) or a pharmaceutically acceptable salt thereof.

11) The method of embodiment 10, wherein the compound of formula (II) is deuterated α-HTBZ or deuterated β-HTBZ.

12) The method according to any of embodiments 1-11, wherein the administration of the specified compound leads to a significant increase in the maximum tolerated dose, a decrease in toxicity, an increase in the half-life (t _1/2 ) or a decrease in the maximum plasma concentration (C _max ) of the minimum effective dose ( MED) compared to administration of an equally effective dose of the corresponding non-deuterated compound.

13) The method according to any of embodiments 1-12, wherein the dyskinesia is of the dystonic type.

14) The method according to any of embodiments 1-13, wherein the dyskinesia is of the choreiform type.

15) The method according to any one of embodiments 1-14, wherein the sick person is a pediatric patient.

16) The method according to any one of embodiments 1-15, wherein the patient's age is from 6 to 18 years.

17) The method of any one of embodiments 1-16, wherein the patient is further administered an additional therapeutic agent.

18) A method of treating dyskinesia due to cerebral palsy in a human patient, comprising administering to the patient a daily amount of deutetrabenazine from about 6 mg/day to about 48 mg/day in one or two doses.

19) The method of embodiment 18, wherein the treatment results in the maintenance or reduction of the patient's abnormal involuntary movements associated with the DCP compared to the patient's abnormal involuntary movements at baseline.

20) The method of embodiment 19, wherein the treatment results in a decrease in the patient's abnormal involuntary movements associated with DCP compared to the patient's abnormal involuntary movements at baseline.

21) The method according to embodiments 19-20, wherein the pathological involuntary movements are measured by at least one of the rating scales:

a) MD-CRS part II;

b) MD-CRS part I;

c) CaGI-I; And

d) CGI-I.

22) The method according to embodiment 21, wherein the reduction in pathological involuntary movements is demonstrated by at least one of the following indicators:

a) reduction in MD-CRS Part II score from baseline to week 15;

b) reduction in MD-CRS Part I score from baseline to week 15;

c) decrease in CaGI-I from baseline to week 15; And

d) decrease in CGI-I score from baseline to week 15.

23) The method of embodiment 21 or embodiment 22, wherein the patient has a MD-CRS Part II total score of >10 at baseline.

24) The method according to any one of embodiments 20-23, wherein the severity of the patient's abnormal involuntary movements is reduced relative to the severity of the patient's abnormal involuntary movements at the baseline level.

25) The method of any one of embodiments 20-24, wherein the patient's motor function is improved compared to the patient's motor function at baseline.

26) The method of embodiment 25, wherein the motor function takes place in the eye and periorbital region, face, tongue and perioral region, neck, torso, upper limb or lower limb, or any combination thereof.

27) The method of any one of embodiments 20-26, wherein the patient's oral/verbal function is improved compared to the patient's oral/verbal function at baseline.

28) The method as in any one of embodiments 20-27, wherein the patient's self-care ability is improved relative to the patient's self-care ability at baseline.

29) The method of any one of embodiments 20-28, wherein the patient's attention/vigilance is improved compared to the patient's attention/vigilance at baseline.

30) The method according to any one of embodiments 20-29, wherein the patient's abnormal movements are significantly or very significantly improved compared to the patient's abnormal movements at baseline.

31) The method of any one of embodiments 18-30, wherein the patient has a Clinical Global Impression of Severity (CGI-S) score of 4 or greater at baseline.

- 15 044015

32) The method of any one of embodiments 20-31, wherein the abnormal involuntary movements associated with dyskinesia in cerebral palsy are reduced by at least 20% compared to the abnormal involuntary movements of the patient at baseline.

33) The method of any one of embodiments 20-32, wherein the patient experiences a decrease in the MD-CRS Part II total score of at least 0.5 points relative to baseline.

34) The method of any one of embodiments 20-32, wherein the patient experiences a decrease in the MD-CRS Part II total score of at least 1 point relative to baseline.

35) The method of any one of embodiments 20-32, wherein the patient experiences a decrease in the MD-CRS Part II total score of at least 2 points relative to baseline.

36) The method of any one of embodiments 20-32, wherein the patient experiences a decrease in the MD-CRS Part II total score of at least 3 points relative to baseline.

37) The method of any one of embodiments 20-32, wherein the patient experiences a decrease in the MD-CRS Part II total score of at least 4 points relative to baseline.

38) The method of any one of embodiments 20-37, wherein the patient experiences a decrease in the MD-CRS Part I total score of at least 2 points relative to baseline.

39) The method of any one of embodiments 20-37, wherein the patient experiences a decrease in the MD-CRS Part I total score of at least 3 points relative to baseline.

40) The method of any one of embodiments 20-37, wherein the patient experiences a decrease in the MD-CRS Part I total score of at least 4 points relative to baseline.

41) The method according to any of embodiments 20-40, and the patient experiences a decrease in the CaGI-I score by at least 0.5 points relative to the initial level.

42) The method according to any of embodiments 20-40, and the patient experiences a decrease in the CaGI-I score by at least 0.6 points relative to the initial level.

43) The method according to any of embodiments 20-40, and the patient experiences a decrease in the CaGI-I score by at least 0.7 points relative to the initial level.

44) The method of any one of embodiments 20-43, wherein the patient experiences a decrease in the CGI-I scale of at least 0.5 points relative to baseline.

45) The method according to any one of embodiments 20-43, wherein the patient experiences a decrease on the CGI-I scale of at least 0.6 points relative to baseline.

46) The method according to any one of embodiments 20-43, wherein the patient experiences a decrease on the CGI-I scale of at least 0.7 points relative to baseline.

47) The method according to any of the previous embodiments, wherein the patient weighs at least 12 kg at baseline.

48) The method of embodiment 47, wherein the patient's initial weight is between 12 kg and <17 kg, and the daily amount of deutetrabenazine administered is less than or equal to about 24 mg, unless the patient has a CYP2D6 disorder; or less than or equal to about 12 mg if the patient has a CYP2D6 disorder.

49) The method of embodiment 47, wherein the patient's baseline weight is between 17 kg and <30 kg, and wherein the daily amount of deutetrabenazine administered is less than or equal to about 30 mg if the patient does not have a CYP2D6 disorder; or less than or equal to approximately 18 mg if the patient has a CYP2D6 disorder.

50) The method of embodiment 47, wherein the patient's baseline weight is between 30 kg and <40 kg, and wherein the daily amount of deutetrabenazine administered is less than or equal to about 42 mg if the patient does not have a CYP2D6 disorder; or less than or equal to approximately 24 mg if the patient has a CYP2D6 disorder.

51) The method of embodiment 47, wherein the patient weighs >40 kg at baseline, and wherein the daily amount of deutetrabenazine administered is less than or equal to about 48 mg if the patient does not have a CYP2D6 disorder; or less than or equal to about 36 mg if the patient has a CYP2D6 disorder

Examples

The following examples are provided to complement the preceding disclosure and to provide a better understanding of the subject matter described herein. These examples should not be construed as limiting the subject matter described. It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be apparent to those skilled in the art and should be incorporated herein and may be made without departing from the true scope disclosures.

Example 1: Efficiency study.

A phase 3, 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of deutetrabenazine is performed as follows.

Approximately 185 patients were randomized to deutetrabenazine versus placebo in a 2:1 ratio (approximately 124 to deutetrabenazine; approximately 61 to placebo), stratified by age at baseline (6 to <12 years; 12 up to 18 years of age inclusive) and region (United States [USA]; excluding US). The sample size is reassessed in the interim analysis (IA) and can be adjusted to approximately 230 patients.

The study population consists of male and female patients aged 6 to 18 years inclusive, diagnosed with DCP.

Patients can only be included in the study if they meet all of the following criteria.

1. The initial age of the patient is from 6 to 18 years (inclusive).

2. The patient's initial weight is at least 12 kg (26 lb).

3. The patient has had symptoms of cerebral palsy (CP) since infancy (<2 years), and the investigator considers CP to be non-progressive (Monbaliu E, et al. Clinical presentation and management of dyskinetic cerebral palsy. Lancet Neurol 2017; 16 (9): 741 -9; Wimalasundera N, Stevenson VL. Cerebral palsy. Pract Neurol 2016; 16: 184-194, incorporated by reference in their entirety).

4. The patient was diagnosed with DCP according to the criteria for Surveillance of cerebral palsy in Europe (Cans, C. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Developmental Medicine & Child Neurology 2000; 42: 816-24, incorporated herein by reference in its entirety).

5. The patient has a total score >10 on MD-CRS Part II items at the first visit, based on the examiner's assessment of chorea.

6. The patient's symptoms are caused by functional problems, as defined by a Clinical Global Impression of Severity (CGI-S) scale of 4 or higher, based on investigator assessment.

7. The predominant movement disorder assessed by EAB at screening is choreiform disorder.

8. The patient may swallow the study drug whole.

9. The patient and caregiver/adult are willing to adhere to the medication regimen and follow all study procedures.

10. The patient is in good general health as demonstrated by the medical and psychiatric history and physical and neurological examination.

11. In the opinion of the investigator, the patient and caregiver/adult are capable of understanding the nature of the study and its procedures, and the patient is expected to complete the study as planned.

12. The patient and guardian/adult provided written informed consent in accordance with local regulations (eg, for patients/adolescents, the patient provides written consent and/or shared consent for patients 14 years of age or older, as appropriate).

13. Women who are postmenarcheal or over 12 years of age can only be included in the study if they have a negative baseline beta-human chorionic gonadotropin test or are infertile.

14. Women who are postmenarcheal or over the age of 12 years whose male partners are potentially fertile (i.e., without vasectomy) should use highly effective methods of birth control throughout the study (i.e., starting at screening) and for 30 days after the last dose of IMP.

Patients will be excluded from participation in this study if they meet any of the following criteria.

1. a. The patient has a predominant movement disorder other than dyskinesia.

b. The patient's predominant motor symptoms are dystonic.

c. The patient's predominant motor symptoms are spastic.

d. The patient has another movement disorder that may impair the MD-CRS Part II motor score.

e. The patient has a choreiform movement disorder that has not been persistent throughout the patient's life.

2. The patient has clinically significant depression at screening or baseline. Patients receiving antidepressant therapy may be included in the study if they have been on a stable dose for at least 6 weeks before screening.

3. The patient has a history of suicidal intent or related behavior within 2 years of assessment:

previous intention to respond to suicidal ideation with a specific plan, regardless of level of ambivalence, at the time of suicidal ideation;

previous suicidal preparatory actions or behavior.

4. The patient has a history of a previous actual, interrupted or blocked suicide attempt.

5. The patient has a first-degree relative who committed suicide.

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6. A patient who is currently receiving, or who has received within the last 4 months prior to the examination, botulinum neurotoxin (BoNT) as part of an investigational clinical trial.

Patients may be included in the study if they receive at least 2 courses of treatment with an FDA-approved drug, BoNT, at regular intervals (eg, every 3 to 4 months), at reasonably stable doses and locations (at the discretion of the investigator), for the treatment of lower extremity spasticity or dystonia, and if expected to continue this stable BoNT injection regimen throughout the study. The patient is expected to continue this stable BoNT injection regimen at regular intervals every 3 months throughout the study. The injection for spasticity or dystonia should be given in a muscle area that is separate from the main areas affected by choreiform movement disorder.

Patients who received BoNT injections more than 4 months before screening and do not plan to continue these injections may be considered for participation in this study.

7. The patient was taking any of the following concomitant medications for dystonia or chorea within the specified exclusion screening windows:

within 3 months: depot antipsychotics, within 30 days: tetrabenazine, deutetrabenazine or valbenazine, within 21 days: reserpine, within 14 days: antipsychotics (oral), typical and atypical antipsychotics, metoclopramide, levodopa, dopamine agonists and monoamine oxidase inhibitors , the use of benzodiazepines, muscle relaxants, trihexyphenidyl, baclofen (oral and intrathecal), gabapentin and levetiracetam is allowed if the dosage has been stable for at least 4 weeks before screening, the use of topiramate (up to 200 mg/day) is allowed if the dosage has been stable in for at least 4 weeks before screening.

8. The patient received stem cell therapy, deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for the treatment of abnormal movements or CP within 6 months of the screening visit, or the patient is not clinically stable.

9. The patient has recently undergone surgery or will undergo a surgical procedure during the study, which in the opinion of the investigator makes the patient unsuitable for the study.

10. The patient has a severe mental disability or an unstable or serious medical condition (eg, epilepsy) at the time of screening or baseline that, in the opinion of the investigator, may compromise or compromise the patient's ability to participate in this study.

11. A patient has a rate-corrected QT interval using the Fridericia formula that is >450 ms on a 12-lead ECG at screening.

12. Patients with a history of flutter-fibrillation, congenital long QT syndrome, bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.

13. The patient has signs of decreased liver function, as shown by the following data:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x the upper limit of normal range (ULN) at screening, alkaline phosphatase (ALT) or total bilirubin >2xULN at screening.

Note. Patients with Gilbert's syndrome are eligible to participate if approved by the medical supervisor.

Note. Patients with abnormalities in 2 or more of the following clinical laboratory parameters must be approved for inclusion in the study by a medical observer: AST, ALT, ALP, and total bilirubin.

14. The patient has evidence of clinically significant renal impairment, as indicated by a serum creatinine level >1.5xULN at screening.

15. The patient has a known allergy to any component of the investigational medicinal product (IMP).

16. The patient participated in an investigational drug or device study and received an IMP/intervention within 30 days or 5 drug half-lives of screening, whichever is greater.

17. The patient is pregnant or breastfeeding.

18. The patient has a history of or acknowledged alcohol or substance abuse in the 12 months prior to the assessment, as defined in the Diagnostic and Statistical Manual of Mental Disorders (version 5).

19. The patient has a positive urine drug test or is unable to abstain.

- 18 044015 to avoid substance abuse throughout the study.

Concomitant therapy or medication use will be monitored throughout the study. Approved medicines are listed in the table below. During the study, you cannot make changes to the dosage. ,__________________________________________________________

Generic/Drug Class Condition Stable medicinal products authorized according to inclusion/exclusion criteria Hormonal contraceptives You must have been on stable treatment (including dose) for at least 3 months before screening. Antidepressants You must be on stable treatment (including dose) for at least 6 weeks before screening. Benzodiazepines, muscle relaxants (including tizanidine), trihexyphenidyl, baclofen (oral and intrathecal), gabapentin and levetiracetam Primary use should not be for dyskinesia; Dosage should be stable for at least 4 weeks before screening. Note: Use of PRN (as needed) is prohibited. Topiramate (up to 200 mg/day) You must be on stable treatment (including dose) for at least 4 weeks before screening. Botulinum toxin May be included in the study if they are receiving at least 2 courses of botulinum neurotoxin (BoNT) treatment at a regular interval (eg, every 3-4 months) at reasonably stable dosages and locations (at the discretion of the investigator) for the treatment of lower extremity spasticity, or dystonia and if expected to continue this stable BoNT injection regimen throughout the study. The injection for spasticity or dystonia should be given in a muscle area that is separate from the main areas affected by choreiform movement disorder. Additional medications permitted with prior approval from a medical supervisor Albuterol, levalbuterol Asthma Guaifenesin Cold symptoms Antihistamines Allergies Melatonin Insomnia Approved strong CYP inhibitors Bupropion Antidepressant (aminoketone) Fluoxetine Antidepressant (selective serotonin reuptake inhibitor) Paroxetine Antidepressant (selective serotonin reuptake inhibitor)

A. The use of these drugs will affect the maximum daily dose of the study drug

CYP=cytochrome P450; PRN=as needed

A medical supervisor will be contacted if the patient is taking (or must start or stop taking during the study) a drug that is associated with QTc prolongation or is a known strong CYP inhibitor. The following drugs are prohibited during the study. Prohibited drugs that have been associated with QT prolongation: azithromycin (up to 500 mg/day allowed), chloroquine/mefloquine, clarithromycin (systemic use prohibited; topical use allowed), domperidone, droperidol, erythromycin (systemic use prohibited; topical use allowed), moxifloxacin, sevoflurane, probucol and sparfloxacin. Prohibited antipsychotic drugs are chlorpromazine, haloperidol, loxapine, molindone, perphenazine, pimozide, prochlorperazine, thioridazine, thiothixene, trifluoperazine, promethazine-containing compounds, carbamazepine, aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, olanza pin/fluoxetine, paliperidone, quetiapine, risperidone, ziprasidone and tiapride.

The primary and secondary objectives and criteria/endpoints of the study are listed below.

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Goals Criteria/Outcomes Main goal study is to evaluate the effectiveness of deutetrabenazine for reducing severity dyskinetic involuntary movements associated with SR. The primary efficacy endpoint is change from baseline in MD-CRS Part II total score to week 15 (movement disorder severity, centrally read) (deutetrabenazine versus placebo). The secondary goal is to evaluate specific parameters of the effectiveness of deutetrabenazine that go beyond the primary purpose. Goals Key secondary efficacy endpoints (deutetrabenazine versus placebo) are as follows: • change in MD-CRS Part I total score (total score, centralized reading) from baseline to week 15, • CaGI-I scale (global, as assessed by caregivers) at week 15, • CGI-Ι scale (global, as assessed by doctors) at 15 weeks. Other efficacy measures and endpoints (deutetrabenazine versus placebo) include the following: • general MD-CRS index (calculated as the sum of MD-CRS I index and II index), • UHDRS-TMS, • UHDRS-TMC, • UHDRS-TMD, Criteria/Outcomes • PEDI-CAT (ADL, Parent/Guardian Complete, Balanced Version), • PedsQL CP module (QoL, patient/carer), • PGI-I scale (global, patient/caregiver), • CGI-S scale (global, assessed by a physician), • CaGI-I response, defined as patients who are described by the caregiver as “much improved” or “much improved” on the CaGI-I scale, • CGI-I response, defined as patients who are described as “much improved” or “significantly improved” on the CGI-I scale, • CGI-S response, defined as patients who have a decrease in CGI-S score of >1 point, • PGI-I response, defined as patients who are described as “much improved” or “somewhat improved” on the PGI-I scale. Secondary target research is to assess safety and tolerability of deutetrabenazine. Safety variables include adverse events (and number of patients withdrawing from the study due to adverse events), vital signs, laboratory tests (hematology, chemistry, and urinalysis), ECG measurements, and CSSRS in children.

ADL=activities of daily living; CaGI-I=caregiver global impression of improvement; CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; CP=cerebral palsy; C SSRS=Columbia Suicidality Severity Rating Scale; ECG=electrocardiogram; MD-CRS I and P = Index I and Index II of the Movement Disorder Rating Scale-Childhood; PEDI-CAT=Pediatric Disability Assessment - Computer Adapted Test; PedsQL=pediatric quality of life analysis; PGI-I=Patient Global Impression of Improvement; QoL=quality of life; UHDRS-TMC=Unified Huntington's Disease Rating Scale - total maximum chorea; UHDRS-TMD=Unified Huntington's Disease Rating Scale - Total Maximum Dystonia; UHDRS-TMS=Unified Huntington's Disease Rating Scale - Total Motor Rating.

General plan of the study.

This is a phase 3, 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of deutetrabenazine administered as oral tablets at a starting dose of 6 mg once daily in patients

- 20 044015 (age 6 to 18 years) with DCP with a predominant choreiform movement disorder who have had non-progressive symptoms of cerebral palsy (CP) since infancy (<2 years). The study will consist of a screening period (up to 31 days) and a double-blind treatment period, including a titration period (7 weeks) and a maintenance period (8 weeks), followed by a washout period of 1 week and a subsequent telephone contact period 1 week after the period washing out. Throughout the study, patients will interact regularly with study site staff, in the clinic, and by telephone (without live video recording) to assess safety/tolerability, severity of dyskinesia, and behavioral status (clinic only).

At the baseline visit (Day 1), patients will be randomized into 2 groups: 1 each to receive investigational drug deutetrabenazine (IMP) or IMP placebo in a 2:1 ratio, with baseline stratification by age (6 to <12 years; 12 to 18 years inclusive) and region (US; non-US). IMP will be titrated during the double-blind treatment period, starting with 6 mg deutetrabenazine or matching placebo IMP in the morning on days 2 and 3, followed by evening administration starting on day 3 until the end of the week (if body weight >40 kg/88 lb). Daily doses of deyetrabenazine 12 mg or higher will be administered in 2 divided equal doses approximately 8 to 10 hours apart throughout the day. The number of eligible IMP placebo tablets will be increased accordingly. After 1 week, the dose can be increased no more often than every 5 days. During the titration period, the IMP dose will be adjusted according to the titration schedule to determine the dose level that optimally reduces dyskinesia (as determined by the investigator, as indicated by a decrease in Clinical Global Impression of Improvement [CGI-I]) and is well tolerated. If a patient experiences a clinically significant IMP-related adverse event, the investigator will first determine whether a dose reduction (to the previous dose level) or interruption is necessary and possible. Once titrated, patients will remain on their optimal dose throughout the maintenance period.

Screening period (up to 31 days): After obtaining informed consent (and written consent and/or joint consent, as appropriate), patients who are medically and psychiatrically stable will undergo a screening assessment, including medical history, physical and neurological examination, laboratory studies, 12-lead electrocardiogram (ECG), and MD CRS Part I and Part II assessments (video recorded, centrally read by the Adjudicated Enrollment Board (EAB)) to assess the severity of dyskinesia, associated symptoms of SD, and behavioral status . Screening may be performed over 2 separate visits at the discretion of the investigator. Diagnosis of CP and DCP is based on clinical features as described in the inclusion/exclusion criteria. The EAB will also confirm, based on video recordings, that choreiformity is clinically the predominant movement disorder in the patient's DCP. The results of the EAB assessment will be available to the investigator prior to study initiation and randomization. At all other visits, the study site physician will administer the MD CRS Part II assessment and videotaped blinded reading.

Titration period (7 weeks). Patients who remain eligible for the study will be randomized at the baseline visit (Day 1) and instructed to take the first dose of blinded IMP the next morning, regardless of food. The titration schedule and maximum dose will be determined by body weight and cytochrome P450 2D6 (CYP2D6) disorder status at baseline. Patients will be classified as having a CYP2D6 disorder if they are receiving a strong CYP2D6 inhibitor or are a poor CYP2D6 metabolizer.

The test IMP will be administered as an oral tablet at a starting dose of 6 mg once daily. Titration schemes based on initial body weight are shown in Table. 1 and 3.

Table 1

Maximum daily dose of IMP during titration period by day and weight category at baseline

Daily dose Observation daya 12 kg to <17 kg (26 lb to <37 lb) 17 kg to <30 kg (37 lb to <66 lb) 30 kg to <40 kg (66 lbs to <88 lbs) >40 kg (>88 lbs) Day 2 6 mg 6 mg 6 mg 6 mg Days 3-7 6 mg 6 mg 6 mg 12 mgb Days 8-14 6 mg 12 mg 12 mg 18 mg Days 15-21 12mg ^s 18 mg 18 mg 24 mg Days 22-28 12mg ^s 18 mg ^s 24 mg ^s 30 mg Days 29-35 18 mg ^s 24 mg ^s 30 mg ^s 36 mg ^s Days 36-42 18mg ^s 24 mg ^s 36 mg ^s 42 mg ^s Days 43-49 24 mg ^s 30 mg ^s 42 mg ^s 48 mg ^s

A. This dose will be administered over the days indicated (inclusive) with clinic visits on days 1, 21 and 49

b. Patients will receive a dose of 6 mg once daily in the morning on days 2 and 3 followed by mg in the evening starting on day 3

With. For those taking strong CYP2D6 inhibitors such as paroxetine, fluoxetine and bupropion, or those who are poor metabolizers of CYP2D6, the maximum daily dose for patients >40 kg is 36 mg/day, for patients 30 to <40 kg 24 mg/day day, for 17 - <30 kg 18 mg/day, and for 12-<17 kg 12 mg/day (see Table 2)

CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product

table 2

Maximum Daily Dose of IMP Based on CYP2D6 Impairment Status

Weight category Maximum daily dose in the absence of CYP2D6 impairment Maximum daily dose for CYP2D6 disorders 12 kg to <17 kg (26 lbs to <37 lbs) 24 mg 12 mg 17 kg to <30 kg (37 lb to <66 lb) 30 mg 18 mg 30 kg to <40 kg (66 lbs to <88 lbs) 42 mg 24 mg >40 kg (>88 lbs) 48 mg 36 mg

CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product

Note. Patients will be classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor or are a poor CYP2D6 metabolizer. Strong CYP2D6 inhibitors include paroxetine, fluoxetine and bupropion.

The maximum daily dose is determined by initial body weight and CYP2D6 impairment status.

Patients and their caregiver/adults will interact weekly with the investigator/staff either through telephone contact (no live video recording) or at a clinic visit from weeks 1 to 7 of the titration period to assess safety/tolerability and determine the dose of IMP that is optimal reduces the severity of dyskinetic involuntary movements (clinically significant reduction in dyskinesia, as indicated by a decrease in CGI-I) and is well tolerated. Clinical assessments of safety/tolerability during titration include assessment of vital signs, monitoring of adverse events and concomitant medications, 12-lead ECG, and rating scales for depression and suicidality. If a patient experiences a clinically significant IMP-related adverse event, the investigator first determines whether a dose reduction (to the previous dose level) or interruption is necessary and possible. At the end of the titration period, the patient's dose will be set to the maintenance period.

In-person (in-clinic) study visits will be scheduled at weeks 3 and 7, and telephone contacts (without live video recording) will be scheduled at weeks 1, 2, 4, 5, and 6 to assess dyskinesia. and side effects. Telephone contacts with the patient will be supported by a real-time video feed without recording to provide the researcher with visual confirmation of verbal information provided by the patient or caregiver. The dose of IMP should be increased weekly to achieve a clinically significant reduction in dyskinesia, as indicated by a decrease in CGI-I. The IMP dose should also not be increased in the following cases: the patient experiences a protocol-defined clinically significant adverse event (defined as an IMP-related adverse event that is of moderate to severe intensity or meets the criteria for a serious adverse event), OR the maximum tolerated dose is reached depending on patient weight and CYP2D6 impairment status at baseline.

The dose can be adjusted up until the clinic visit at week 7 inclusive. If the optimal dose is reached before the 7th week of the clinic visit, the IMP dose should not be increased further, but the patient should continue on this dose for the remainder of the titration period and throughout the maintenance period. If a patient experiences a clinically significant IMP-related adverse event, the investigator will first determine whether a dose reduction (to the previous dose level) or interruption is necessary and possible. If the decision that the patient requires a dose reduction or interruption is made during the telephone contact, this should be followed by an unscheduled clinic visit as soon as possible.

Maintenance period (8 weeks): Patients will continue to receive the maintenance dose for the next 8 weeks, although a 1-fold dose reduction (to the level of the previous dose for the remainder of the study) is allowed in the event of side effects. Patients will return to the clinic at weeks 9, 12 and 15 to assess efficacy and safety.

Wash-out period and follow-up: All patients will stop taking IMP at week 15 and return 1 week later for the end-of-study visit. Patients who complete the study may be eligible to enter an open-label extension safety study. Patients not participating in the open-label safety extension study will have a safety follow-up telephone contact 1 week after the end of the washout period (2 weeks after their last IMP dose (week 17)).

When approximately 90 patients complete the study (including follow-up), an independent data monitoring committee (iDMC) will conduct a non-blinded IA for futility and re-evaluate the sample size based on the centrally read MD CRS Part II. Based on the IA results, the study may be stopped, or the sample size may be maintained as planned (approximately 185 patients total) or increased (to approximately 230 patients). An iDMC policy will be developed for IA, and procedures to ensure the integrity of the study will be included in the policy.

At the time of obtaining informed consent, the parent/legal guardian will be informed that after randomization to treatment, patients must remain in the study and complete all study procedures unless an election is made to withdraw consent. Patients who drop out of the study before completing the 15-week treatment period should receive an early termination (ET) visit as soon as possible after taking the last dose of IMP. All patients who discontinue prematurely will have a telephone follow-up to assess safety 2 weeks after the last dose of IMP; Scores will be as described for Week 17.

Primary and secondary assessments

The primary outcome is the difference in mean values between deutetrabenazine and placebo in the target patient population for change from baseline to week 15 in the centrally read part II MD-CRS, regardless of whether a dose reduction, interruption, or discontinuation occurred, and regardless from treatment-related side effects.

Secondary outcome measures are differences in mean scores between deutetrabenazine and placebo in the target patient population for (1) change from baseline to week 15 in the centrally administered Movement Disorder Rating Scale-Childhood Part I (MD-CRS Part I); (2) caregiver global impression of health improvement (CaGI-I) at week 15; and (3) CGI-I at week 15, regardless of whether dose reduction, interruption, or discontinuation occurred and regardless of treatment-related adverse events.

The primary evaluation evaluates the effectiveness of choreiform movement reduction in DCP patients with a predominant choreiform movement disorder, focusing on the causal effects associated with IMP. Secondary assessments assess the patient's ability to perform activities of daily living and improvement in dyskinesia symptoms as assessed by the caregiver and investigator, with a focus on causal effects associated with IMP.

The patient population for this study is DCP patients with a predominant choreiform movement disorder and DCP severity represented by a MD CRS Part II total score >10 at baseline. This population is expected to have the sensitivity to demonstrate clinically significant improvement following treatment with deutetrabenazine. For practical reasons, it is not possible to obtain a central reading of MD-CRS Part II items at the baseline visit prior to randomization to determine whether the patient is eligible for the study. Therefore, inclusion in the study is based on the investigator's assessment of the MD-CRS Part II items at baseline. Patients who do not meet the MD-CRS Part II criterion based on the central reading will be excluded from the primary analysis set (i.e., leaving a modified trial population [mITT] that contains only patients with a total score > 10 MD-CRS Part II items at the baseline visit, based on centrally read scores).

Primary outcome analysis

The primary endpoint is change from baseline to week 15 in centrally read MD-CRS Part II (deutetrabenazine versus placebo).

The mITT analysis (for all patients with a centrally read total score >10 on MD-CRS Part II items at baseline and at least 1 after the baseline centrally read MD-CRS II assessment) will be used for the primary analysis.

The primary analysis will be a repeated measures mixed model with change in MD-CRS Part II total score as the dependent variable. The model will include fixed effects for treatment group, week (3 levels: weeks 9, 12, and 15), and treatment group by week interactions. Baseline MD CRS Part II total score, age group at baseline (2 levels: 6 to <12 years; 12 to 18 years), and region (United States; non-United States) will be included as covariates. An unstructured covariance model will be used.

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Missing data will be classified as missing at random (MAR) or missing not at random (MNAR). Intermittent missing data and ETs for patients who are lost to follow-up or who are excluded for reasons other than tolerability, adverse events, or lack of efficacy will be classified as MAR. All other early terminations will be classified as MNAR. Classification as MAR/MNAR will be done blindly before IA and before database locking. The MAR/MNAR multiple imputation method will be used in the primary analysis, where the MNAR data will be imputed using the cross-reference method and the MAR data will be imputed based on the randomized treatment group. Each of the resulting full, imputed data sets will be analyzed using the analysis model described above, and the resulting statistics will be combined using the methodology presented in the Rubin DB papers. Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & Sons, and Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2002, New York: John Wiley & Sons, incorporated herein by reference in its entirety.

The difference in least squares (LS) means of change in MD-CRS Part II total score from baseline to week 15 (deutetrabenazine versus placebo) will be compared using a one-sided test for superiority at a nominal significance level of α=0.025.

The mean LS and standard error for treatment groups, the difference in mean LS, two-sided 95% confidence interval, and p value for the comparison (deutetrabenazine versus placebo) at week 15 will be presented.

Key secondary endpoints and analysis

Key secondary endpoints are listed below.

1. Change from baseline to week 15 in the centrally read portion of the IMD-CRS (deutetrabenazine versus placebo).

2. CaGI-I at week 15 (deutetrabenazine versus placebo).

3. Clinical Global Impression of Improvement (CGI-I) at week 15 (deutetrabenazine versus placebo).

Each key secondary outcome measure will be analyzed in the same way as in the primary analysis, except that the baseline value of that outcome measure will be included as a covariate.

Other performance indicators/outcome indicators

Other efficacy measures and endpoints (deutetrabenazine versus placebo) include the following:

Global MD-CRS Index (calculated from MD-CRS Part I and Part II), Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS), Unified Huntington's Disease Rating Scale - Total Maximum Chorea (UHDRS-TMC), Unified Scale Huntington's Disease Rating - Total Maximum Dystonia (UHDRS TMD), Pediatric Disability Rating - Computer Adapted Test (PEDI CAT) (Activities of Daily Living, Parent/Carer Completion, Counterbalanced Version), CP Module from Pediatric Quality of Life Inventory (PedsQL) ( quality of life, patient/caregiver), Patient Global Impression of Improvement ([PGI-I] global, patient/caregiver), Clinical Global Impression of Severity ([CGI-S], clinician-rated global), CaGI response- I, defined as patients whose condition is described by the caregiver as much improved or very much improved on the CaGI-I scale, CGI-I response, defined as patients whose condition is described as much improved or very much improved on the CGI-I scale, CGI response -S, defined as patients who have a decrease in CGI-S score of <1 point, PGI-I response, defined as patients described as significantly improved or slightly improved on the PGI-I score.

Multiple comparisons and multiplicity

The primary efficacy outcome will be tested at a one-sided significance level of α=0.025.

If the primary outcome is statistically significant (p value <0.025), 3 key secondary hypotheses will be tested using a hierarchical approach at a one-sided significance level of α=0.025 in the following order: (1) MD-CRS Part I, (2) CaGI- I and (3) CGI-I.

If the primary outcome is not statistically significant, confirmatory hypothesis testing will not be conducted for the secondary hypotheses and they will be considered exploratory rather than confirmatory.

If the secondary outcome is not statistically significant, confirmatory hypothesis testing will not be performed on the next secondary hypothesis/hypotheses and it/they will be considered exploratory rather than confirmatory.

No multiplicity controls will be applied to sensitivity analyzes or other endpoints.

Planned interim review

When approximately 90 patients complete the study (including follow-up), iDMC will perform a non-blinded IA for futility and re-evaluate the sample size based on the centrally read part II of the CRS MD.

Re-estimation of sample size will be performed using the promising zones approach (Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a practical guide with examples. Stat Med 2011; 30 (28): 3267-84, fully included in this description by reference). The IA will estimate conditional power for the initially planned sample size of approximately 185 patients given the observed data, and the sample size may be increased to an overall maximum of approximately 230 patients.

Type I error rates will be monitored using the method of Chen, DeMets and Lan (Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is promising. Stat Med 2004; 23 (7): 1023-38, incorporated herein by reference in its entirety); therefore, α=0.025 will be used for the primary analysis.

Security analyzes

The security analysis will be performed on the security analysis suite.

All adverse events will be coded using the Medical Dictionary of Regulatory Activities. Each patient will be counted only once in each preferred term or system organ category for safety analysis. Summary data will be presented for all adverse events (overall and by severity), adverse events determined by the investigator to be related to the study IMP (i.e., reasonable possibility) (defined as related or not related) (overall and by severity ), serious side effects and side effects leading to exclusion from the study. Results will be presented by treatment group and for all patients. Lists of patients with serious adverse events and adverse events leading to discontinuation will be presented.

Changes in laboratory, ECG, and vital sign findings will be summarized descriptively. All values will be compared to predefined criteria to identify potentially clinically significant values or changes, and such values will be listed.

Concomitant medication use will be summarized by therapeutic class using descriptive statistics.

Frequency and severity of suicidal ideation or behavior as measured by the Children's Columbia Suicide Rating Scale (C-SSRS) questionnaire will be presented for all patients aged >12 years by visit and by treatment group. A table of shifts will be presented for children's C-SSRS categories at baseline versus the worst (highest) category during the treatment period.

Drug-induced parkinsonism will be assessed according to the Extrapyramidal Symptom Rating Scale (ESRS) (subscales I (Subjective Questionnaire) and II (Parkinsonism/Akathisia Rating)). (See, for example, Chouinard G, Margolese NS. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research 2005; 76: 247-65, incorporated herein by reference in its entirety.) The ESRS is administered at the time of screening; baseline; and weeks 3, 7, 9, 12, 15/ET and 16/EOS. Subscale I of the ESRS assesses subjective parkinsonism/akathisia at periods other than the day of assessment during the past 7 days. Scoring occurs on a 4-point scale (0=absent, 1=mild, 2=moderate or 3=severe). The assessment takes into account the patient's verbal report of 1) the frequency and duration of the symptom during the day, 2) the number of days the symptom was present in the last week, and 3) the patient's subjective assessment of the intensity of the symptom. Subscale II of the ESRS Parkinsonism and Akathisia Questionnaire includes 17 items with scores ranging from 0 to 102 to assess the following: tremor (0-48), gait and posture (0-6), postural stability (0-6), rigidity (0-6). 24), expressive automatic movements (0-6), bradykinesia (0-6) and akathisia (0-6).

Assessment of behavior change will be conducted according to the Children's Behavior Checklist (CBCL) questionnaire. See, for example, the works of Achenbach TM, Ruffle TM. Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies. Pediatr Rev 2000; 21 (8): 265-71; Achenbach TM. Advancing assessment of children and adolescents: commentary on evidence-based assessment of child and adolescent disorders. J Clin Child Adolesc Psychol 2005; 34: 541 7, incorporated herein by reference in its entirety. The complete CBCL consists of two parts: the competency scale (parts I to VII) and the syndrome scale (behavioral items). The Competency Scale (Parts I to VII) assesses a variety of activities (eg, sports, hobbies, games, organizations, clubs, teams, groups, work and housework), interpersonal relationships, and academic performance. The syndrome scale includes 25 044015 118 questions related to problem behavior. This study will use a recall period now or within the last week, representing a change from the baseline scale that was now or within the last 6 months. For each item, the parent/guardian will circle 0 if the item does not match their child, 1 if the item is somewhat or sometimes true, and 2 if the item is very or often true. The CBCL is part of the Achenbach Empirical Scoring System, which defines syndromes, which are behavioral clusters that indicate specific types of behavioral, social, or emotional problems. Problem behavior is assessed across the following 8 empirically based syndromes: anxiety/depression, withdrawal/depression, somatic complaints, social problems, thinking problems, attention problems, rule-breaking behavior, and aggressive behavior. Competency and syndrome scales are displayed in profiles based on gender and age percentiles and T-scores based on national normative samples. A full CBCL (Competency and Syndrome Scale) assessment will be completed at screening and at 15 weeks/ET. Only the CBCL syndrome scale will be completed at baseline, 3, 7, 9, 12, and 16 weeks/EOS.

Sedation will be assessed using the Epworth Sleepiness Scale (ESS). (See, for example, Johns MW. The assessment of sleepiness in children and adolescents. Sleep Biol Rhythm 2015; 13 (Suppl. 1): 97, incorporated herein by reference in its entirety.) The ESS is a self-administered questionnaire consisting of 8 questions that assess a patient's overall level of daytime sleepiness. ESS is administered during screening; at baseline and weeks 3, 7, 9, 12, 15/ET, and 16/EOS. The ESS asks respondents to rate on a 4-point Likert scale (0-3; 0=never will fall asleep; 1=slight chance of falling asleep; 2=medium chance of falling asleep; 3=high chance of falling asleep) their usual chances of dozing off or falling asleep in various situations or activities. that most people do in their daily lives. The ESS total score is the sum of the 8-item scores and can range from 0 to 24, with higher scores indicating higher levels of daytime sleepiness.

For continuous variables, descriptive statistics will be provided for actual values and changes from baseline to each time point. For categorical variables, the number of patients and percentages will be provided. Narrative summaries of serious adverse events, patient attrition due to adverse events, and potentially clinically significant abnormal findings (clinical laboratory or vital signs) based on predefined criteria will also be provided.

If any patient dies during the study, a list of deaths will be provided and all relevant information will be discussed in the patient profile included in the clinical study report.

Tolerability analysis

If more than 15% of patients drop out of the study before the end of the treatment period, the number of days until study discontinuation will be analyzed using Kaplan-Meier methodology using the ITT analysis set.

Pharmacokinetic/pharmacodynamic analysis

Samples collected for pharmacokinetic analysis will be quantified for deutetrabenazine and alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (βHTBZ) as the active metabolites of deutetrabenazine and other metabolites as appropriate. The sum of α-HTBZ and β-HTBZ will be calculated based on individual concentrations. Concentrations of deutetrabenazine and metabolites (individually and in total) can be analyzed using population pharmacokinetic methods. Exploratory pharmacokinetic/pharmacodynamic analysis can be performed on pharmacodynamic/safety endpoints using all relevant accumulated pharmacokinetic/pharmacodynamic data from studies of deutetrabenazine.

results

Treatment with deyetrabenazine has been shown to be safe and effective. Treatment with deyetrabenazine resulted in significant improvements in all primary and secondary endpoints.

Patients receiving deutetrabenazine demonstrated a significant reduction in MD-CRS Part II total score of approximately 0.5 to 4 points (compared with placebo) from baseline to week 15, thereby demonstrating an improvement in DCP associated with deutetrabenazine.

Patients receiving deutetrabenazine also demonstrated a significant reduction in the MD-CRS Part I total score of approximately 2 to 4 points (compared to placebo) from baseline by week 15, thereby demonstrating an improvement in DCP associated with deutetrabenazine.

Patients receiving deutetrabenazine also demonstrated a significant reduction in CaGI-I score of approximately 0.5 to 0.7 points (compared to placebo) from baseline by week 15, thereby demonstrating an improvement in DCP associated with deutetrabenazine.

Patients receiving deutetrabenazine also show a significant reduction in

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CGI-I was approximately 0.5 to 0.7 points (versus placebo) from baseline by week 15, thereby demonstrating the improvement in DCP associated with deutetrabenazine.

Patients receiving deutetrabenazine also demonstrate improvement based on significant reductions in the Unified Huntington's Disease Rating Scale - Total Motor Score (UHDRS-TMS), or the Unified Huntington's Disease Rating Scale - Total Maximum Chorea (UHDRS-TMC), or the Unified Huntington's Disease Rating Scale - Total Maximal Chorea (UHDRS-TMC) score. Huntington's Disease - Total Maximum Dystonia (UHDRS TMD) scores, or the CP module of the Pediatric Quality of Life Inventory (PedsQL) (quality of life, patient/caregiver).

Patients receiving deutetrabenazine also demonstrate improvement on the Pediatric Assessment Disability Inventory Computer Adapted Test (PEDI CAT) (Activities of Daily Living, Parent/Carer Occupation, Content Balanced Version).

Patients receiving deutetrabenazine also demonstrate a CaGI-I response, defined as patients who are described by the caregiver as being much improved or very much improved on the CaGI-I scale.

Patients receiving deutetrabenazine also demonstrate a CGI-I response, defined as patients who are described as significantly improved or very much improved on the CGI-I scale.

Patients receiving deutetrabenazine also demonstrate a CGI-S response, defined as patients who experience a decrease of <1 point on the CGI-S scale.

Patients receiving deutetrabenazine also demonstrate a PGI-I response, defined as patients who are described as significantly improved or slightly improved on the PGI-I score.

The safety of deutetrabenazine treatment will be demonstrated by the Children's Columbia Suicide Rating Scale (C-SSRS), Extrapyramidal Symptom Rating Scale (ESRS), Children's Behavior Checklist (CBCL), Epworth Sleepiness Scale (ESS), and absence of serious adverse events.

Example 2: Open-label extension study.

A phase 3, 55-week, open-label, single-individual, long-term study of the safety, tolerability, and efficacy of deyetrabenazine for the treatment of dyskinesia in cerebral palsy in children and adolescents is conducted as follows.

General Study Design: Patients who successfully completed a 21-week phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of deutetrabenazine (pivotal study) may be eligible for inclusion in this study after completion of 1- week washout period and final assessment at 16 weeks. This study will include children and adolescents aged 6 to 18 years at the time of their enrollment in the original study.

Screening. Screening assessments for this open-label study will be performed as part of the baseline visit. Any adverse event that began after the end of the parent study and was recorded after informed consent/consent for this open-label study will be recorded in this study.

Day 1 Visit: For all patients, the Week 16 baseline study visit may be the Day 1 open study visit. Open-label study Day 1 assessments, which are identical to the baseline study week 15/16 visit assessments, whichever is most relevant, do not need to be repeated, with the exception of orthostatic heart rate and blood pressure, which need to be repeated on Day 1.

Titration period (7 weeks): Because patients in the parent study discontinued treatment with deutetrabenazine for at least 1 week after completion of the parent study or received placebo in the parent study, all patients will undergo a dose titration of deutetrabenazine in this study to maintain blinding of the parent study. Patients will receive 6 mg of deyetrabenazine on the morning of day 2. The titration schedule and maximum dose are consistent with the dose in the original study.

Maintenance period (46 weeks): At the end of the titration period, the patient's starting dose for the maintenance period (weeks 8 to 53) will be established. Dose adjustments of deutetrabenazine (up or down) can be made during the maintenance period if necessary, but not more often than every 5 days and only in 6 mg increments. As with titration, dose adjustments should be made based on all available information. It is possible to reduce the dose of deutetrabenazine or adjust it for patients based on side effects or tolerability data. During the maintenance period, in-person (in-clinic) study visits will be scheduled at weeks 14, 27, 40, and 53 to assess safety and effectiveness, and telephone contacts (with video without live recording) will be scheduled at weeks 21, 33, and 46 for in order to evaluate side effects and dyskinesia. At week 53/ET, patients will undergo a full assessment including vital signs and weight, physical and neurological examination, height measurement, 12-lead ECG, safety laboratory tests, urine drug screening, and beta-chorionic gonadotropin (β-HCG), if applicable, and MD-CRS parts I and II, CaGI-I, CGI-I, CGI-S, PEDI-CAT, UHDRS-TMS, SORM, C-SSRS scores in children, ESRS (subscales I and

II), CBCL and ESS.

Wash-out and follow-up period: All patients discontinue deutetrabenazine at week 53 and return 1 week later (week 54) for safety assessment. Patients will have a follow-up telephone contact (without live video streaming) for safety assessment 1 week after the end of the washout period (2 weeks after the last dose of deutetrabenazine (week 55).

Primary and secondary objectives and study criteria/outcomes are provided below.

Goals Criteria/Outcomes The primary objective of this study is to evaluate the safety and tolerability of long-term therapy. deutetrabenazine in children and adolescents with DCP. The safety parameters/endpoints are as follows: • adverse events, • vital signs, • C-SSRS in children, • ECG parameters, • clinical and laboratory parameters (hematology, serum chemistry and urine analysis), • ESRS (subscales I and II), • CBCL, ESS The secondary objective of this study is to evaluate the effectiveness of long-term deutetrabenazine therapy in reducing the severity of DCP. The performance criteria/outcomes are as follows: • MD-CRS Part I total score (as assessed by the physician), • MD-CRS Part II total score (as assessed by the physician), • global MD-CRS index (calculated based on the total scores of MD-CRS parts I and II), • CaGI-I (Global, Guardian Rated), • CGI-Ι (global, assessed by a physician), • CGI-S (global, physician assessed), • PEDI-CAT (Activities of Daily Living, Nursing Complete, Content Balanced Version), • UHDRS-TMS (as assessed by a physician), • SORM (according to the doctor's assessment).

CaGI-I=caregiver's overall impression of improvement; CBCL=Child Behavior Checklist (for children 6 to 18 years); CGI-I=Clinical Global Impression of Improvement; CGIS=Clinical Global Impression of Severity; COPM=Canadian Labor Productivity Measure; C-SSRS=Columbia Suicide Severity Rating Scale; DCP=dyskinesia in cerebral palsy; ECG=electrocardiogram; ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS=Epworth Sleepiness Scale (Children and Adolescents); MD-CRS=Movement Disorder Rating Scale-Childhood; PEDI-CAT=Pediatric Disability Assessment - Computer Adapted Test; UHDRSTMS=Unified Huntington's Disease Rating Scale - Total Motor Score.

Patients can only be included in the study if they meet all the criteria listed below.

1. The patient has completed the initial study (Example 1 above).

2. The patient weighs at least 12 kg (26 lb) on Day 1 of this study.

3. The patient can swallow the deyetrabenazine tablet whole.

4. The patient and caregiver are willing to adhere to the deyetrabenazine regimen and comply with all study procedures.

5. The patient is in good general health as demonstrated by the medical and psychiatric history and physical and neurological examination.

6. In the opinion of the investigator, the patient and caregiver are capable of understanding the nature of the study and its procedures, and the patient is expected to complete the study as planned.

7. For a minor patient, parents/legal guardians provide written informed consent and the patient provides assent (in accordance with local law). Adult patients (in accordance with local law) provide their own written informed consent.

8. The caregiver provides written informed consent after the adult patient has assigned the role, or if the role has been delegated by the minor patient's parent/legal guardian.

9. Women who are postmenarcheal or over 12 years of age can only be included in the study if they have a negative β-HCG test result on day 1 or have no

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10. Women who are postmenarcheal or over 12 years of age whose male partners are potentially fertile (i.e., without vasectomy) should use highly effective methods of birth control throughout the study (i.e., starting on day 1) and within 30 days after the last dose of deyetrabenazine.

Patients will be excluded from participation in this study if they meet any of the following criteria.

1. On the first day of this study, the patient experiences clinically significant depression.

2. The patient has a history of suicidal ideation or related behavior: a previous intention to act in response to suicidal ideation in a specific manner, regardless of the level of ambivalence, at the time of suicidal ideation.

3. The patient has a history of a previous actual, aborted, or aborted suicide attempt.

4. The patient has a first-degree relative who committed suicide.

5. A patient who is currently receiving or has received botulinum neurotoxin (BoNT) as part of an investigational clinical trial.

6. The patient was taking any of the following concomitant medications for dystonia or chorea within the specified exclusion windows on Day 1 of this study:

within 3 months: depot antipsychotics, within 30 days: tetrabenazine or valbenazine, within 21 days: reserpine, within 14 days: antipsychotics (oral), typical and atypical antipsychotics, metoclopramide, levodopa, dopamine agonists and monoamine oxidase inhibitors,

7. The patient has received stem cell therapy, deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation to treat abnormal movements or MR, or the patient is not clinically stable.

8. The patient has recently undergone surgery or is expected to undergo surgery during the study, which in the opinion of the investigator makes the patient unsuitable for the study.

9. The patient has a severe mental disability or an unstable or serious medical condition (eg, epilepsy) that, in the opinion of the investigator, may jeopardize or compromise the patient's ability to participate in this study.

10. The patient has a QT interval (QTc) corrected for heart rate using the Fridericia formula (QTcF) reading >450 ms on the 12-lead ECG on day 1 of this study.

11. Patients with a history of flutter-fibrillation, congenital long QT syndrome, bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.

12. The patient has signs of liver failure, as evidenced by the following:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5x the upper limit of normal range (ULN) on day 1 of this study, alkaline phosphatase (ALP) or total bilirubin (Tbil) >2xULN on day 1 of this study.

13. The patient has evidence of clinically significant renal impairment, as indicated by a serum creatinine >1.5x ULN on day 1 of this study.

14. The patient is allergic to any of the components of deyetrabenazine.

15. The patient participated in an investigational drug or device study other than the parent study and received an IMP/intervention for 30 days or 5 half-lives of the drug on Day 1 of that study, whichever is greater.

16. The patient is pregnant or breastfeeding.

17. The patient has a history of or admits to alcohol or substance abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V™).

18. The patient has a positive urine drug test or is unable to abstain from substance abuse throughout the study.

results

Long-term administration of tolerable amounts of deutetrabenazine has been shown to reduce abnormal involuntary movements associated with dyskinesia in cerebral palsy, with a favorable safety profile.

Example 3: Efficacy Study in Adults.

A phase 3 study to evaluate the efficacy and safety of deutetrabenazine is being conducted in a population of male and female patients diagnosed with DCP. Patients can only be included in the study if they meet all of the following criteria.

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Claims (11)

1. The patient was initially over 18 years of age. 2. Symptoms of cerebral palsy (CP) in the patient since infancy (<2 years). 3. The patient has been diagnosed with DCP according to the European Cerebral Palsy Surveillance Criteria. 4. The patient has a total score >10 on the MD-CRS Part II items at the first visit based on the examiner's assessment of chorea. 5. The patient's symptoms are caused by functional problems, as defined by a Clinical Global Impression of Severity (CGI-S) scale of 4 or higher, based on investigator assessment. 6. The predominant movement disorder assessed by EAB at screening is choreiform disorder. Patients will receive 6 to 48 mg of deutetrabenazine. The titration schedule and maximum dose are the same as in the original study, Example 1, above. results Administration of appropriate amounts of deutetrabenazine to adult patients has been shown to reduce abnormal involuntary movements associated with dyskinesia in cerebral palsy, with a favorable safety profile. Example 4: Efficiency Study. A phase 3 study to evaluate the efficacy and safety of deutetrabenazine is being conducted in a population of male and female patients diagnosed with DCP. Patients can only be included in the study if they meet all of the following criteria. 1. The initial age of the patient is from 6 to 18 years (inclusive). 2. Symptoms of cerebral palsy (CP) in the patient since infancy (<2 years). 3. The patient has been diagnosed with DCP according to the European Cerebral Palsy Surveillance Criteria. 4. The patient has a total score >10 on the MD-CRS Part II items at the baseline visit, based on the examiner's assessment of chorea. 5. The patient's symptoms are caused by functional problems, as defined by a Clinical Global Impression of Severity (CGI-S) score of 4 or higher, based on investigator ratings. 6. The patient's predominant motor symptoms are dystonic. Patients will receive 6 to 48 mg of deutetrabenazine. The titration schedule and maximum dose are the same as in the original study, Example 1, above. results Administration of tolerable amounts of deutetrabenazine to pediatric patients has been shown to reduce dystonic abnormal involuntary movements associated with dyskinesia in cerebral palsy, with a favorable safety profile. Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention, and that such changes and modifications can be made without departing from the spirit of the disclosure. It is therefore intended that the appended claims cover all such equivalent variations that fall within the true spirit and scope of the disclosure. CLAIM 1. A method of treating dyskinesia in cerebral palsy in a human patient in need of treatment, comprising administering to the patient 6 mg/day to 48 mg/day, in one or two doses, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each position represented by D has a deuterium enrichment of at least 10%, wherein the treatment results in the maintenance or reduction of the abnormal involuntary movements associated with dyskinesia in cerebral palsy in the patient, compared with the abnormal involuntary movements of the patient on baseline level. 2. The method according to claim 1, where pathological involuntary movements associated with dyskinesia during cerebrovascular disease - 30 044015 rib palsy, belong to the dystonic type. 3. The method according to claim 1, where the pathological involuntary movements associated with dyskinesia in cerebral palsy are of the choreiform type. 4. The method according to any one of the preceding claims, wherein the sick person is a pediatric patient. 5. The method according to any of the preceding claims, wherein the pathological involuntary movements associated with dyskinesia in cerebral palsy are measured using at least one of the rating scales: a) MD-CRS part II; b) MD-CRS part I; c) CaGI-I; and d) CGI-I. 6. The method according to any of the previous paragraphs, where the initial weight of the patient is at least 12 kg. 7. The method according to claim 6, wherein the patient's initial weight is from 12 kg to <17 kg and the daily amount of deutetrabenazine administered is less than or equal to 24 mg, if the patient does not have a cytochrome P450 2D6 (CYP2D6) disorder; or less than or equal to about 12 mg if the patient has a CYP2D6 disorder. 8. The method according to claim 6, where the patient's initial weight is from 17 kg to <30 kg and the daily amount of deutetrabenazine administered is less than or equal to 30 mg, if the patient does not have a CYP2D6 disorder; or less than or equal to about 18 mg if the patient has a CYP2D6 disorder. 9. The method according to claim 6, where the patient's initial weight is from 30 to <40 kg and the daily amount of deutetrabenazine administered is less than or equal to 42 mg, if the patient does not have a CYP2D6 disorder; or less than or equal to 24 mg if the patient has a CYP2D6 disorder. 10. The method of claim 6, wherein the patient's baseline weight is >40 kg and the daily amount of deutetrabenazine administered is less than or equal to 48 mg, unless the patient has a CYP2D6 disorder; or less than or equal to approximately 36 mg if the patient has a CYP2D6 disorder. I. A method of treating dyskinesia in cerebral palsy in a human patient in need of treatment, comprising administering to the patient 6 mg/day to 48 mg/day, in one or two doses, of a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each position, designated as D, has a deuterium enrichment of at least 10%, where the treatment results in the persistence or reduction of abnormal involuntary movements associated with dyskinesia in cerebral palsy in the patient, compared to the abnormal involuntary movements of the patient at baseline. 12. The method of any one of the preceding claims, wherein each position represented by D has a deuterium enrichment of at least 50%, at least 90%, at least 95%, at least 98%, or at least 99%. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2