EA042209B1 - METHOD FOR TREATMENT OF PATHOLOGICAL INVOLVED MOVEMENTS - Google Patents

Description

The present invention relates to a method for switching a person from tetrabenazine to deutetrabenazine for the treatment of chorea associated with Huntington's disease, where the method includes:

a) cancellation of the daily amount of tetrabenazine;

b) the next day, administering to the person an initial daily amount of deutetrabenazine, wherein the daily amount of tetrabenazine is 12.5 mg and the initial total daily amount of deutetrabenazine is 6 mg;

the daily amount of tetrabenazine is 25 mg, and the initial total daily amount of deutetrabenazine is 12 mg;

the daily amount of tetrabenazine is 37.5 mg, and the initial total daily amount of deutetrabenazine is 18 mg;

the daily amount of tetrabenazine is 50 mg, and the initial total daily amount of deutetrabenazine is 24 mg;

the daily amount of tetrabenazine is 62.5 mg, and the initial total daily amount of de- utetrabenazine is 30 mg;

the daily amount of tetrabenazine is 75 mg, and the initial total daily amount of deutetrabenazine is 36 mg;

the daily amount of tetrabenazine is 87.5 mg and the initial total daily amount of deutetrabenazine is 42 mg or the daily amount of tetrabenazine is 100 mg and the initial total daily amount of deutetrabenazine is 48 mg.

In some embodiments of the present invention, the degree of chorea control is improved as a result of the transition, as indicated by a decrease of at least 0.5 points on the total chorea score scale (TMS). The improvement is measured from baseline to the level of maintenance therapy.

In some embodiments of the present invention, the transition leads to a reduction in chorea by at least 15%.

In some embodiments of the present invention, (i) the transition results in a reduction in chorea of at least 10%, and said method also provides for one or more of the following conditions:

motor function improves by at least 10%;

the physical functioning of the object is improved;

swallowing improves;

balance does not deteriorate;

treatment does not cause a significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia and the maximum increase in QTcF is less than 5 ms;

or:

(ii) motor function is improved by at least 10% and said method also provides for one or more of the following:

chorea is reduced by at least 10%;

the physical functioning of the object is improved;

swallowing improves;

balance does not deteriorate;

treatment does not cause a significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism, or dysphagia, and the maximum increase in QTcF is less than 5 ms.

In a preferred embodiment of the present invention, the initial daily dose is 12, 18, 24, 30, 36, 42, or 48 mg and the initial daily dose is administered in two doses.

In some embodiments of the present invention, the first dose is 6 mg and the second dose is 6 mg; the first dose is 9 mg and the second dose is 9 mg; the first dose is 12 mg and the second dose is 12 mg;

the first dose is 15 mg and the second dose is 15 mg; the first dose is 18 mg and the second dose is 18 mg;

the first dose is 21 mg and the second dose is 21 mg or the first dose is 24 mg and the second dose is 24 mg.

In a preferred embodiment of the present invention, the method further comprises:

c) after about one week, determine the degree of control of abnormal involuntary movements achieved with the initial daily dose of deutetrabenazine, and the tolerability of the initial daily dose of deutetrabenazine; And

d) increasing the daily dose of deutetrabenazine by 6 mg/day to a subsequent daily dose of deutetrabenazine if switching does not result in at least maintenance of chorea control and the initial daily dose is tolerable.

In some embodiments of the present invention, the method further comprises:

e) after about one week, repeat steps c) and d) in those people in whom abnormal involuntary movements are reduced and the daily amount of deutetrabenazine is well tolerated.

In some embodiments of the present invention, the method is to reduce the amount of deutetrabenazine by 6 mg/day to a subsequent daily amount in those individuals in whom any subsequent daily amount is intolerable. Moreover, the method additionally includes repeating step e) until the degree of control of abnormal involuntary movements becomes adequate, and the daily amount of deutetrabenazine is tolerable.

In some embodiments of the present invention, the initial daily dose is 6 mg and is administered as a single dose.

In some embodiments of the present invention, the initial daily amount of deutetraben-3 042209 zine is 6, 12, 18, 24, 30, 36, or 42 mg, further comprising:

c) after about one week, determine the degree of control of abnormal involuntary movements achieved with the initial daily dose of deutetrabenazine, and the tolerability of the initial daily dose of deutetrabenazine; And

d) increasing the daily dose of deutetrabenazine by 6 mg/day to a subsequent daily dose in those people in whom switching does not result in at least maintenance of chorea control and the initial daily amount is tolerable.

Moreover, the subsequent daily amount is 12, 18, 24, 30, 36 or 42 mg, additionally including:

e) after about one week, repeat steps c) and d) in those patients in whom abnormal involuntary movements have decreased and the daily dose of deutetrabenazine is tolerable.

In this case, it is preferable when the daily dose is 18, 24, 30, 36 or 42 mg, additionally including the repetition of step e) until the degree of control over abnormal involuntary movements becomes adequate, and the daily dose of deutetrabenazine is tolerated. Moreover, the total maximum daily dose is 48 mg or the total maximum daily dose is 36 mg.

In this case, it is preferable when a person simultaneously receives a strong inhibitor of CYP2D6. In particular, a strong inhibitor of CYP2D6 is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet or ritonavir, most preferably a strong inhibitor of CYP2D6 is paroxetine, fluoxetine or bupropion.

In some embodiments of the present invention, the daily amount of tetrabenazine is 12.5 mg and the initial total daily amount of deutetrabenazine is 6 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 25 mg and the initial total daily amount of deutetrabenazine is 12 mg.

In this case, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 6 mg and the second dose being 6 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 37.5 mg and the initial total daily amount is increased by 6 mg/day to a subsequent daily amount of deutetrabenazine of 18 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 9 mg and the second dose being 9 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 50 mg and the initial total daily amount of deutetrabenazine is 24 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 12 mg and the second dose being 12 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 62.5 mg and the initial total daily amount of deutetrabenazine is 30 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 15 mg and the second dose being 1.5 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 75 mg and the initial total daily amount of deutetrabenazine is 36 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 18 mg and the second dose being 18 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 87.5 mg and the initial total daily amount of deutetrabenazine is 42 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 21 mg and the second dose being 21 mg.

In some embodiments of the present invention, the daily amount of tetrabenazine is 100 mg and the initial total daily amount of deutetrabenazine is 48 mg.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is administered in two doses, with the first dose being 24 mg and the second dose being 24 mg.

In some embodiments of the present invention, the transition results in at least maintaining control of chorea in humans.

In some embodiments of the present invention, the initial total daily amount of deutetrabenazine is 6, 12, 18, 24, 30, or 36 mg. Preferably, however, the individual is simultaneously receiving a strong inhibitor of CYP2D6, which is preferably fluoxetine, paroxetine, bupropion, quinidine, cinacalcet or ritonavir, most preferably paroxetine, fluoxetine or bupropion.

Connections

Tetrabenazine (Nitoman, Xenazine, Ro 1-9569), 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2methylpropyl)-2H-benzo[a]quinoline, is an inhibitor of vesicular monoamine transporter 2 (VMAT2). Tetrabenazine is commonly prescribed for the treatment of Huntington's disease (Savani et al., Neurology 2007, 68(10), 797, Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), 7-17). Tetrabena

- 4 042209 zine is subject to extensive oxidative metabolism, including O-demethylation of methoxy groups, and hydroxylation of the isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655). Adverse effects associated with the administration of tetrabenazine include neuroleptic malignant syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia, agitation, confusion, orthostatic hypotension, nausea, dizziness, depression, and parkinsonism. O

I

Tetrabenazine

Deuterium-Rich Tetrabenazine Analogs d6-Tetrabenzazine (equivalent, deutetrabenazine, SD-809 or DTBZ) is a deuterated analog of tetrabenazine currently in clinical development. US 8524733, US 20100130480 and US 20120003330.

o ^N *

D ₃ CO'^ d6-Tetrabenazine (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2Н-benzo [a]quinolysin-2 he

In all methods and compositions described herein using deutetrabenazine, deutetrabenazine can be administered or formulated as part of a pharmaceutical composition, wherein the composition has an enrichment in deuterium of at least 90% at each of the positions indicated by D. In some embodiments, the composition has an enrichment at least 95% deuterium at each of the positions labeled D. In some embodiments, the composition has a deuterium enrichment of at least 98% at each of the positions labeled D.

In humans, as shown below, d6-tetrabenazine is rapidly and extensively converted in the liver (similar to non-isotopically enriched tetrabenazine) to the main active metabolites of dihydrotetrabenazine (HTBZ), called d6-a-HTBZ and d6-p-HTBZ (as a mixture + and - isomers) that have the structures shown below (+ isomers). It is believed that these metabolites determine clinical efficacy.

CD _a CD _a d6-a-HTBZ 66-β-ΗΤΒΖ

Kinetic isotope effect of deuterium

Deuterium (D) is a naturally occurring, non-radioactive, stable isotope of hydrogen (H) that contains both a proton and a neutron in the nucleus. The presence of a neutron doubles the mass of D compared to H, which in turn increases the vibrational frequency of the CD covalent bond compared to the CH covalent bond. An increase in the vibration frequency of a covalent bond leads to an increase in the activation energy required to break this bond, and, as a consequence, to an increase in the strength of the bond. This increased strength of the covalent bond can in some cases alter the kinetics of covalent bond cleavage, leading to the so-called kinetic isotope effect (KIE). Under certain specific conditions, which are associated with various quantum mechanical aspects of covalent bond cleavage, the replacement of a CH covalent bond with a CD covalent bond can lead to a significant KIE of deuterium. A large deuterium KIE for a drug that is a CYP450 substrate can in some cases lead to improved pharmacokinetic parameters of that drug, potentially leading to differentiation between deuterated and non-deuterated drugs. The CD covalent bonds in deutetrabenazine satisfy a number of chemical and biological criteria that work together to provide a deuterium KIE that is large enough to slow the O-demethylation of deutetrabenazine's active metabolites relative to tetrabenazine. It is important to note that the magnitude of this deuterium KIE cannot be predicted a priori, and therefore it is not possible to know in advance whether replacing the CH covalent bond in tetrabenazine with a CD covalent bond will result in noticeable and/or improved biological differences.

Deutetrabenazine or d6-tetrabenazine is a VMAT2 inhibitor.

In d6-tetrabenazine, six hydrogen atoms are replaced by deuterium atoms, as shown in the figure above. There is substantial evidence that d6-tetrabenazine forms stable covalent bonds and that its trideuteromethyl group (-CD ₃ ) is a covalently bound stable moiety with no difference or qualification of this bond compared to the methyl group (-CH3 ).

First, the covalent nature of the CD bond can be established using spectroscopic techniques such as infrared (IR) spectroscopy. The characteristic IR absorption of CD stretching vibrations in the range of approximately 2000-2300 cm ^-1 (Miller and Corcelli, 2009), which is often used by researchers as site-specific and non-perturbative probes for protein studies (Miller and Corcelli, 2009; Zimmermann et al. , 2011). d6-Tetrabenazine has distinct IR absorptions at 2060-2250 cm ^-1 which are related to the CD stretching vibrations. These absorption bands are absent in the IR spectrum of the non-deuterated form of tetrabenazine.

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

Third, the deuterium atoms in d6-tetrabenazine are not exchanged with hydrogen under normal physiological conditions. The pKa of unconjugated aliphatic CH bonds is in the range of 45-50, which means that at equilibrium the ratio of dissociated to undissociated species is less than 10-45. In comparison, the CH bonds of the methoxy groups of tetrabenazine, and hence the CD bonds of the methoxy groups of d6-tetrabenazine, are even less acidic, with a pKa value approaching 50. This means that the pH of an aqueous solution must be increased to more than 45 before any of the deuterium atoms in deutetrabenazine can start an exchange with hydrogen atoms.

Finally, d6-tetrabenazine or deutetrabenazine has been administered to humans in clinical studies and subjected to various in vitro incubations with several enzymatic processes. Known active metabolites and subsequent downstream metabolites are monitored in in vitro incubates and/or in human plasma by LC/MS/MS methods. These metabolites were synthesized and confirmed to contain the expected trideuteromethyl groups (-CD3), confirming that the C-D covalent bonds in deutetrabenazine are stable and are transferred to downstream deutetrabenazine metabolites. Deutetrabenazine has a differentiated pharmacokinetic profile compared to d0tetrabenazine.

Due to the deuterium kinetic isotope effect (KIE), substitution of H for D in the CH covalent bond in a small molecule preparation has the potential to impair drug metabolism (Baillie, 1981) as it requires more energy to be cleaved by enzymes such as, for example, cytochrome isoenzymes P450 (CYP450). The KIE value of deuterium varies depending on the nature of the C-H bond to be destroyed and whether the cleavage of this bond is the rate-limiting step in the oxidative metabolism of the drug by the CYP isoenzyme.

Thus, by attenuating metabolism, half-life (t1/2), exposure (AUC [plasma area under the curve of plasma level versus time]), and peak plasma concentration (Cmax) can be changed relative to the non-deuterated form of the drug (Kushner et al., 1999; Baillie, 1981). The substitution of D for H at certain positions in the drug also has the potential to attenuate the degradation of deuterium-containing metabolites of the deuterated parent drug. Many deuterium substitutions at key oxidative metabolic sites have no effect; thus, empirical data is needed to determine whether deuteration has potentially relevant in vivo results. Tetrabenazine contains numerous C-H covalent bonds that are subject to oxidative metabolism by CYP450 enzymes. For all of the above reasons, a drug with a longer half-life can lead to greater efficacy, better safety and tolerability, improved quality of life, and potential cost savings in the long run. Different deuteration profiles can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) reduce the number of doses required to achieve the desired effect, (d) reduce the number of doses required to achieve the desired effect , (e) increase the formation of active metabolites, if any, (f) reduce the formation of harmful metabolites in certain tissues, and/or (g) provide a more effective drug and/or a safer drug for polypharmacy, whether polypharmacy intentional or not. The deuteration approach has demonstrated the ability to slow the metabolism of tetrabenazine and reduce interpatient variability.

Abbreviations and definitions

To facilitate understanding of the disclosure, a number of terms and abbreviations used in this document are defined below:

All publications and references cited in this document are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found either in the included publications or sources and expressly set forth or defined in this document, the definitions of the terms or the meanings expressly set forth in this document will control in all respects.

When ranges of values are disclosed and the notation n1... to n2 or n1-n2 is used, where n1 and n2 are numbers, then, unless otherwise noted, this notation is intended to include the numbers themselves and the ranges in between. This range may be integral or continuous between and including the final values.

The term and/or when used in a list of two or more elements means that any of the listed elements may be used alone or in combination with any one or more of the listed elements. For example, the expression A and/or B is intended to mean one or both of A and B, that is, A only, B only, or A and B in combination. The term A, B and/or C is intended to mean A only, B only, C only, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

The term approximately, as used herein when referring to a measurable quantity such as compound amount, dose, time, temperature, etc., is intended to cover variations of 20, 10, 5, 1, 0.5%, or even 0 .1% of the indicated amount.

As used herein, the term pathological refers to an activity or feature that is different from a normal activity or feature.

As used herein, the term abnormal muscle activity refers to muscle activity that differs from muscle activity in a healthy subject. Pathological activity may be reduced or increased compared to normal activity. An increase in muscle activity can lead to excessive pathological movements, excessive normal movements, or a combination of both.

The term adverse event (AE) means any adverse medical event in a patient who has been administered a drug, whether or not it has a causal relationship with that treatment. Thus, an adverse event can be any undesirable and unintended physical sign, symptom, or laboratory parameter that develops or worsens in severity during the course of this study, or a significant worsening of the study disease or any comorbidity, whether or not considered to be study related. medicine. A new condition or worsening of a pre-existing condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that occurred prior to study entry and did not worsen during this study will not be considered adverse events. Weak AEs are those that do not limit the activity of the object; moderate AEs are those that cause some limitation in normal activities; and heavy AEs are those that render the subject unable to perform normal actions.

A treatment-related adverse event is an adverse event that, in the opinion of a physician or clinician, is related to the prescribed drug. Such a definition should be understood as often not a yes/no question, but may lie on a continuum in which the AE is more or less likely to be related to treatment, including the proximity of the occurrence of the event to dose administration, the disappearance of the AE upon discontinuation or reduction in drug dose. means and failure of other factors (eg, pre-existing conditions, environmental factors, etc.) to explain AE.

The term CYP2D6 inhibitor refers to a drug that inhibits CYP2D6, therefore making it unavailable for the metabolism of other substrate compounds; Co-administration of a drug metabolized by CYP2D6 with a CYP2D6 inhibitor should be done with caution and often at a reduced dosage, as plasma concentrations of the drug will often be present. Inhibitors of CYP2D6 include amiodarone, celecoxib, chloroquine, chlorpromazine, cimetidine, citalopram, clomipramine, codeine, deiavirdin, desipramine, dextropropoxyphene, diltiazem, doxorubicin, entacapone (high dose), fluoxetine, fluphenazine, fluvaxamine, haloperidone, lobistinalo , mibefradil, moclobemide, nortuloxelin, paroxetine, perphenazine, propafenone, quinacrine, quinidine, ranitidine, risperidone, ritonavir, serindole, sertraline, thioridazine, valproic acid, venlafaxine, vinblastine, vincristine, vinorelbine, and yohimbine. Strong CYP2D6 inhibitors include fluoxetine, aroxetine, bupropion, quinidine, cinacalcet, and ritonavir.

The term degree, as used herein in relation to the control of abnormal muscle activity or abnormal involuntary movements (eg, chorea), is synonymous with level.

As used herein, the term disorder is generally synonymous and interchangeable with the terms disease, syndrome, and condition (as in a medical condition), as they all reflect a pathological condition of the human or animal body, or one of its parts, that impairs normal functioning, usually manifested by distinguishing between signs and symptoms.

The terms treat and treatment are intended to alleviate or eliminate a disorder or one or more of the symptoms associated with the disorder; or alleviating or eliminating the cause(s) of the disorder itself. As used herein, reference to treating a disorder includes prevention.

The terms prevent and prevent refer to a method of delaying or eliminating the occurrence of a disorder; and/or its accompanying symptoms, preventing the subject from acquiring the disorder or reducing the risk of acquiring the disorder.

The terms tolerable and tolerable refer to the amount of deuterium-substituted tetrabenazine (eg, deutetrabenazine) or other drug (eg, deuterium-substituted VMAT inhibitor or valbanazine) that results in a low incidence of adverse events such as drowsiness, irritability, fatigue, vomiting, and nausea in patients and when adverse events do not result in a reduction in the dose of deuterium-substituted tetrabenazine or other drug, in the temporary suspension of deuterium-substituted tetrabenazine or other drug, or in the withdrawal of deuterium-substituted tetrabenazine or other drug. Deuterium-substituted tetrabenazine is also considered tolerable if any underlying symptoms such as depression, anxiety, suicidality, parkinsonism in patients with diseases or conditions such as Huntington's disease, tardive dyskinesia, or Tourette's syndrome do not worsen. Tolerable and tolerable should also refer to that amount of deutetrabenazine (or other drug, if applicable) that does not require downward adjustment in the usual (e.g. daily) dose or dose interruption, e.g. due to adverse events. The amount to be tolerated may vary between subjects and also within a subject over the course of a disease or course of treatment.

The term adequate, as used herein in relation to the control of abnormal muscle activity or pathological involuntary movements (eg, chorea) in a subject, refers to the level of control that is observable and satisfactory for the subject. The clinician, investigator, in consultation with the subject, will determine when an adequate level of control of abnormal muscle activity or abnormal involuntary movements (eg, chorea) has been achieved. In general, the adequacy of the level of control of abnormal muscle activity or pathological involuntary movements provided by the amount of drug will depend on the tolerance of that amount and will often be the maximum tolerated value that gives an observed increase in control (optimal amount). The amount of deutetrabenazine may be increased weekly with adequate control of chorea, with the subject undergoing a protocol that defines a clinically significant adverse event (defined as related to investigational drug) as either a) moderate or severe in intensity, or b) meeting the criteria for a serious adverse event ( SAE) or the maximum allowable dose has been reached. The appropriate level may vary between subjects, and also within the course of a disease or course of treatment.

The phrases improve, improved, reduce, reduced, etc., are used in relation to the level, degree or amount by which some quality is reduced, improved, etc. in an object or objects by treatment with a compound, in comparison with the object or objects without treatment. Otherwise, if explicitly stated, these phrases may be compared to the subject or subjects receiving standard treatment. Such measures can be made by reference to an appropriate scale or score known in the art (see, for example, the examples provided herein for Disorder-Control and/or Disorder-Relief Endpoint Scales and Likert Scales).

The term pathological involuntary movement, as used herein, includes involuntary movements associated with movement disorders.

The term subject refers to an animal, including, but not limited to, primate (e.g., humans, monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, etc.), lagomorphs, pigs (eg, pigs, miniature pigs), horse, dog, cat, and the like. The terms object and patient are used interchangeably in this regard with respect to, for example, a mammalian object such as a human patient.

GTS-QOL consists of two parts. The first part is typically twenty-seven questions assessing various aspects of how the tics affect the subject's life, each rated on a five-point scale: no problem, minor problem, moderate problem, distinct problem, or severe problem. Subscales that combine some of these aspects may focus on, for example, the Physical Activity/Activity of Daily Living (ADL) subscale. The second part is a simple rating of the object's life satisfaction, where 100 is extremely satisfied and 0 is extremely dissatisfied.

Physical Functioning Scale SF-36. The SF-36 is a 36-item short health survey used to assess health-related quality of life (Ware, 1996). SF-36 has been useful for comparing specific populations and comparing the relative burden of various diseases. An evaluation of SF-36, which was performed in HD patients, was shown to have robust design validity and repeat test reliability, and was able to discriminate between age-related controls and normative data on a 10-item scale of physical functioning (Ho, 2004). The study included a full assessment of SF-36, with the Physical Functioning Scale (also known as PF-10) analyzed as a secondary endpoint. The Physical Functioning Scale is a subset of the 10 SF36 items that examine the subject's perceived health-related limitations in physical activity. The SF-36 Physical Functioning Score is a 10-item scale by which subjects rate their ability to perform normal physical activities such as walking, climbing stairs, bathing, or dressing. Given that chorea can interfere with basic motor skills, gait and walking, it is not surprising that subjects with more impaired function would benefit more from this score.

Tourette Syndrome Patient's Overall Clinical Impression of Disease Severity (TS-PGIS) is a new five-point scale in which 1 indicates no tics, 2 indicates mild tics (non-anxious, noticeable, or interfere with daily life), 3 indicates moderate tics (can be disturbing, noticeable, and sometimes interfering with daily life), 4 indicates marked tics (very disturbing, noticeable, and interfering with daily life), and 5 indicates severe tics (extremely disturbing, always noticeable, and interfering with most daily activities).

The tick-free interval is a five-point scale where 1 indicates an interval of at least one day after the last tick, 2 indicates an interval of 6 hours to less than one day since the last tick, 3 indicates an interval of between 1 hour and less than 6 hours after the last tick, 4 indicates the interval between 5 minutes to less than 1 hour after the last tick, and 5 means less than 5 minutes after the last tick.

The TS-CGI is a seven-point scale assessed by the clinician in which 1 indicates normal or absent tics, 2 indicates that tics may or may not be present, 3 indicates mild, observable motor and/or phonic tics that may be noticeable or not noticeable, will not draw attention to the individual and are not associated with a disorder or impairment, 4 indicates mild observable motor and/or phonic tics that will always be noticeable, draw attention to the person and may be associated with some disorder or impairment, 5 indicates marked, excessive motor and/or phonic tics that are destructive, always draw attention to the individual, and are always associated with significant distress or impairment, 6 indicates severe, grossly excessive motor and/or phonic tics that are destructive, always draw attention to the individual and are associated with injury or inability to perform daily activities nctions, and 7 - extreme, disabling tics.

YGTSS is a comprehensive assessment of the various aspects and severity of motor and phonic tics. In one aspect, each of the five categories—number, frequency, intensity, complexity, and interference—is scored from 0 to 5 for both motor and phonic tics, creating a 0 to 25 tic severity scale for each of the phonic tic severity scales ( VTSS) and the Motor Tic Severity Scale (MTSS). Collectively, they include the Overall Tic Severity Scale (TTS). Separately, deterioration in a patient's life is rated on a scale of 0 to 50, with 0 indicating no deterioration, 10 being minimal, 20 moderate, 30 moderate, 40 marked, and 50 severe deterioration, giving a deterioration scale. When a deterioration scale is added to the TTS, this constitutes the full global severity scale (GSS) from the YGTSS.

Tourette Syndrome Global Patient Dynamics Assessment (TS-PGIC) is a seven-point scale in which -3 indicates very poor, -2 indicates fairly poor, -1 indicates marginally poor, 0 indicates no change, 1 indicates marginally improved , 2 indicates significant improvement, and 3 indicates strong improvement.

GTS-QOL consists of two parts. The first part is typically twenty-seven questions assessing various aspects of how the tics affect the subject's life, each rated on a five-point scale: no problem, minor problem, moderate problem, noticeable problem, or severe problem. The second part is a simple rating of the object's life satisfaction, where 100 is extremely satisfied and 0 is extremely dissatisfied.

The tick-free interval is a five-point scale where 1 indicates an interval of at least one day after the last tick, 2 indicates an interval of 6 hours to less than one day since the last tick, 3 indicates an interval of between 1 hour and less than 6 hours after the last tick, 4 indicates an interval between 5 minutes to less than one hour after the last tick, and 5 means less than 5 minutes after the last tick.

The term VMAT2 refers to the vesicular monoamine transporter 2, an integral membrane protein that acts to transport monoamines, in particular neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from the cellular cytosol to synaptic vesicles.

The term VMAT2-mediated disorder refers to a disorder characterized by abnormal VMAT2 activity. The VMAT2-mediated disorder may be wholly or partly mediated by modulation of VMAT2. In particular, a VMAT2-mediated disorder is one in which inhibition of VMAT2 results in some effect on the underlying disorder, eg, administration of a VMAT2 inhibitor results in some improvement in at least some of the patients being treated.

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The term VMAT2 inhibitor, VMAT2 inhibition, or VMAT2 inhibition refers to the ability of a compound described herein to alter VMAT2 function. A VMAT2 inhibitor can block or reduce VMAT2 activity by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2, or by forming a non-covalently bound complex. Such inhibition may only occur in particular cell types or may be dependent on a particular biological event. The term VMAT2 inhibitor, VMAT2 inhibition, or VMAT2 inhibition also refers to altering VMAT2 function by reducing the likelihood that a complex is formed between VMAT2 and a natural substrate.

The compounds disclosed herein may exist as therapeutically acceptable salts. As used herein, the term therapeutically acceptable salt is salt forms or zwitterionic forms of the compounds disclosed herein that are therapeutically acceptable as defined herein. Salts can be obtained during the final isolation and purification of the compounds, or separately by reacting the appropriate compound with the appropriate acid or base. Therapeutically acceptable salts include acids and base addition salts.

Suitable acids for use in preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(IS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid acid, dodecylsulfuric acid, ethane-1,2disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, chlorine hydrohydric acid, hydroiodic acid, (+)-E-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-E-malic acid, malonic acid, (±)-DLmandelic acid acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, ptoluenesulfonic acid, undecylenic acid and valeric acid.

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

While it is possible that the compounds of the present invention may be administered as the starting chemical, it is also possible to provide them as a pharmaceutical composition. Accordingly, this document provides pharmaceutical compositions that include one or more of the specific compounds described herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. . The correct composition depends on the chosen route of administration. Any of the known methods, carriers, and excipients, as appropriate and contemplated in the art, may be used; for example, Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be prepared by any method known in the art, such as by conventional mixing, dissolving, granulating, panning, triturating, emulsifying, encapsulating, encapsulating, or compressing methods. Pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed, sustained, extended, sustained, sustained, controlled, accelerated and rapid, targeted, programmed release, and gastric retention dosage forms. These dosage forms can be obtained with

- 10 042209 in accordance with conventional methods and techniques known to those skilled in the art (Compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical ( including dermal, buccal, sublingual and intraocular) administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. typically, these methods include the step of bringing into association a compound of the present invention, or a pharmaceutical salt, prodrug or solvate (active ingredient) thereof, with a carrier which comprises one or more accessory ingredients.In general, compositions are prepared by uniformly and thoroughly combining the active ingredient with liquid carriers or finely divided solid carriers, or both, followed, if necessary, by shaping the product into the desired composition.

Formulations of the compounds described herein suitable for oral administration may be presented as separate units such as capsules, sachets or tablets, each containing a given amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical formulations that can be used orally include tablets, hard gelatin capsules, and soft, sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or moulding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as powder or granules, optionally mixed with binders, inert diluents or lubricating, surfactant or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound wetted with an inert liquid diluent. Tablets may optionally be coated or formulated with a break line and may be formulated to provide slow or controlled release of the active ingredient from them. All formulations for oral administration should be in dosages suitable for such administration. Hard capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fixed oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquers and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablet or dragee coatings to identify or characterize various combinations of active compound doses.

The compounds may be formulated for parenteral administration by injection, for example by bolus administration or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formative agents such as suspending, stabilizing and/or dispersing agents. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored as a powder or in a lyophilized state requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Single injectable solutions and suspensions can be prepared from the sterile powders, granules and tablets described above.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain antioxidants, buffers, bacteriostatic and solutes that make the drug isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to provide highly concentrated solutions.

- 11 042209 ditch.

In addition to the formulations previously described, the compounds may also be formulated as a depot formulation. Such long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated using suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, lozenges or gels prepared in the usual manner. Such compositions may include the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

The compounds may also be formulated as rectal compositions such as suppositories or retention microenemas, for example containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

Certain compounds disclosed herein may be administered topically, that is, by non-systemic administration. This includes applying a compound disclosed herein to the outside of the epidermis or buccal cavity and instilling such compound into the ear, eye and nose such that the compound does not substantially enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin at the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

For administration by inhalation, the compounds can be delivered by insufflator, pressurized spray packs, or other convenient aerosol spray delivery methods. Pressurized packages may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by using a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of the invention may take the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder can be administered using an inhaler or insufflator.

Preferred unit formulations are compositions containing an effective dose as indicated below, or an appropriate fraction of the active ingredient thereof.

The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg/kg per day. The dosage range for adults is usually 5 mg to 2 g/day. Tablets or other forms of presentation that are provided in discrete units may conveniently contain an amount of one or more compounds that is effective at or is a multiple of that dosage, for example, units containing 5 to 500 mg, typically about 10, 200 mg .

The amount of active ingredient that may be combined with carrier materials to form a single dosage form will vary depending on the host to be treated and the particular route of administration.

In some embodiments, the compounds disclosed herein may be formulated or administered using any of the formulations and methods disclosed in US Patent Application No. 14/030322, filed September 18, 2013, which is incorporated herein by reference in its entirety.

The compounds may be administered by various routes, for example orally, topically or by injection. The attending physician will be responsible for the exact amount of the compound administered to the patient. The specific dosage level for any particular patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, exact disorder being treated. , and its severity. In addition, the route of administration may vary depending on the disorder and its severity.

In the event that the patient's condition does not improve, then at the physician's discretion, the administration of the compounds may be administered chronically, i.e., for an extended period of time, including throughout the life of the patient, to improve or otherwise control or limit the symptoms of the patient's disorder.

In the event that the patient's condition improves, at the discretion of the physician, the administration of the compounds may be continuous or may be temporarily suspended for a certain period of time (ie drug holidays).

After the patient's condition improves, if necessary, a maintenance dose is administered.

- 12 042209

Subsequently, the dosage or frequency of administration, or both, may be reduced depending on the symptoms to a level at which the improved condition is maintained. However, patients may require intermittent treatment on a long-term basis for any recurrence of symptoms.

Disclosed herein are methods of treating a VMAT2-mediated disorder, comprising administering to a subject having or suspected of having such a disorder a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

VMAT2-mediated disorders include, but are not limited to, chronic hyperkinetic movement disorders, Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette's syndrome, depression, malignancy, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and/or any disorder that can be ameliorated, ameliorated or prevented by administration of a VMAT2 inhibitor.

Also disclosed herein are methods for treating abnormal muscle activity, pathological involuntary movements, or movement disorders, comprising administering to a subject having or suspected of having such a disorder, a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. facilities.

Movement disorders include akathisia, akinesia, ataxia, athetosis, ballism, bradykinesia, cerebral palsy, chorea, corticobasal degeneration, dyskinesia (eg, paroxysmal), dystonia (general, segmental, focal), including blepharospasm, graphospasm (limbic dystonia), laryngeal dystonia (spasmodic dysphonia) and oromandibular dystonia, essential tremor, geniospasm, hereditary spastic paraplegia, Huntington's disease, multiple system atrophy (Shy Drager's syndrome), myoclonus, Parkinson's disease, levodopa-induced dyskinesia of Parkinson's disease, parkinsonism, progressive supranuclear palsy, restless leg syndrome , Rett syndrome, spastic torticollis (cervical dystonia), post-stroke spasticity, cerebral palsy, multiple sclerosis, spinal cord or brain injury, stereotypic movement disorder, stereotypy, Sydenham's chorea, synkinesis, tardive dyskinesia, tics, Tourette's syndrome, and disease Wilson.

Plasma levels of a compound described herein, or its metabolites, can be measured using the methods described by Li et al. Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950; Jindal, et al., Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7; Schwartz, et al., Biochemical Pharmacology 1966, 15(5), 645-55; Mehvar, et al., Drug Metabolism and Disposition 1987, 15(2), 250-5; Roberts et al., Journal of Chromatography, Biomedical Applications 1981, 226(1), 17582; and in any publications mentioned there or using any modifications made based on them.

Примеры изоформ цитохрома Р450 у объекта млекопитающего включают, но не ограничиваются ими, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

Examples of monoamine oxidase isomers in a mammalian subject include, but are not limited to, MAOA and MAOB.

Cytochrome P450 isoform inhibition is measured by the method of Ko et al. (British Journal of Clinical Pharmacology, 2000, 49, 343-351). MAOA isoform inhibition is measured by the method of Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). MAOB isoform inhibition is measured by the method of Uebelhack et al. (Pharmacopsychiatry, 1998, 31, 187-192).

Examples of polymorphically expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYp2c9, CYP2C19, and CYP2D6.

The metabolic activities of liver microsomes, cytochrome P450 isoforms, and monoamine oxidase isoforms are measured by the methods described herein.

Examples of improved outcomes in controlling the disorder and/or eliminating the disorder or improved clinical outcomes include, but are not limited to:

b) improved performance of the Unified Huntington's Disease Rating Scale (UHDRS);

c) improved scores on the Total Maximal Chorea Rating Scale (TMS) UHDRS;

d) improved performance on the UHDRS Total Mobility Scale (TMS);

e) improved scores on the Patient's Overall Impression of Progress (PGIC) scale;

f) improved scores on the Clinical Global Impression of Conditions (CGIC) scale;

g) improved scores on the Unified Parkinson's Disease Rating Scale, including a score for dysarthria;

- 13 042209

h) improved scores on the Pathological Involuntary Movement Scale (AIMS);

i) improved Goetz dyskinesia scores;

j) improved performance of the Unified Dyskinesia Rating Scale;

k) improved scores on the PDQ-39 questionnaire on Parkinson's disease;

(l) Improved primate general dyskinesia scores;

m) improved performance of the Berg Equilibrium Rating Scale;

n) improved scores on the SF-36 Physical Functioning Scale;

o) reduced scores on the Hospital Anxiety and Depression Rating Scale (HADS);

p) reduced scores on the Colombian Suicidal Severity Scale (C-SSRS);

q) Improved Swallowing Problem Questionnaire (SDQ) scores;

r) improved (reduced) Barnes Akathisia Rating Scale (BARS) scores;

s) reduced scores on the Epworth Sleepiness Rating Scale (ESS);

t) Improved Modified Cranial and Servical Dystonia Score 24 (CDQ-24);

u) Montreal Cognitive Assessment (MCA);

v) Improved Yale Global Tic Severity Scale (YGTSS) scores, including motor tic severity, vocal tic severity, general tic worsening (TTS), and global tic severity (GSS);

w) improved (reduced) cumulative tick severity (TTS);

x) Improved Tourette Syndrome Clinical Global Impression (TS-CGI) scores;

y) improved scores for assessing the patient's overall impression of the severity of Tourette's syndrome (TSPGIS);

z) Childhood Depression Inventory 2 (CDI-2, parental versions and self-reports);

aa) Columbian Child Suicidal Severity Scale (C-SSRS);

bb) Yale-Brown Childhood Obsessive-Compulsive Disorder Scale (CY-BOCS);

cc) Gilles de la Tourette Syndrome - Quality of Life (GTS-QOL) including Daily Physical/Activity Subscale score, Visual Analogue Scale (VAS) General Life Satisfaction Index, Psychological Assessment Subscale, Obsessive-Compulsive Assessment Subscale and/or Evaluation her cognitive subscale.

Examples of diagnostic endpoints of hepatobiliary function include, but are not limited to, alanine aminotransferase (ALT), serum glutamate pyruvate transaminase (SGPT), aspartate aminotransferase (AST or SGOT), ALT/AST ratios, (ALP), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (GGTP, γ-GTP, or GGT), leucine aminopeptidase (LAP), liver biopsy, liver ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to indicated normal levels as specified in the Diagnostic and Laboratory Test Reference, 4th edition, Mosby, 1999. These tests are performed by accredited laboratories according to standard protocol.

In addition to being useful in human treatment, some of the compounds and compositions described herein may also be useful in the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs and cats.

General synthetic methods for the preparation of compounds

The compounds disclosed herein can be prepared by methods known to the person skilled in the art and routine modifications thereof, and/or the following procedures similar to those described in US 20100130480 (paragraphs [0012]-[0121]), US 20120003330 (paragraphs [0010 ]-[0062]), W02005077946; WO2008/058261; EP 1716145; Lee et al., J. Med. Chem., 1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldt et al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org. Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiat. Isot., 1993, 44 (4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873; Ivanov et al., Heterocycles 2001, 55 (8), 1569-1572; US 2830993; US 3045021; W02007130365; WO 2008058261, which are incorporated herein in their entirety and the references therein and their usual modifications.

Isotopic hydrogen can be introduced into the compound, as described herein, by synthetic methods using deuterated reagents, whereby the degree of incorporation is predetermined; and/or exchange methods, where the degree of incorporation is determined by the equilibrium conditions and can vary greatly depending on the reaction conditions. Synthetic methods in which tritium or deuterium is directly and specifically inserted using tritiated or deuterated reagents of known isotopic abundance may yield high abundance of tritium or deuterium, but may be limited by the required chemistry. On the other hand, exchange methods can result in lower incorporation of tritium or deuterium, often with the isotope distributed over many regions of the molecule.

In some embodiments, specific examples of compounds of the present invention include a compound selected from the list described in paragraph [0122] US 20100130480 and paragraph

- 14 042209

[0163] US 20120003330, which are incorporated into the present description by reference.

Changes in the in vitro metabolic properties of some of the compounds described herein, compared to their non-isotopically enriched counterparts, and methods for determining such changes, are described in paragraph [0125] US 20100130480 and paragraphs [0165]-[0185] - US 20120003330, which are incorporated herein by reference.

Lineups

Compounds may be formulated for use in the dosing regimens and methods disclosed herein using methods known in the art, for example, as described in US 2014/336386. Examples of these compositions are given below.

mg d6-tetrabenzazine gastroerosive sustained release (small tablet) (Formulation A). In table. 1 below discloses the elements for a 350 mg total weight gastroerosive granular tablet formulation containing 15 mg (RR, SS) 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-( 2methylpropyl)-2H-benzo[a]quinolizin-2-one.

Table 1

material mg/tab % c( ₆ -tetrabenzazine (crushed) 15.0 4.3 Mannitol Powder 185.4 53.0 Microcrystalline cellulose 61.8 17.7 PVP К29/32 14.0 4.0 Tween 80 (Polysorbate 80) 3, 8 1.1 Mannogem® EZ (spray dried mannitol) 31.5 9.0 POLYOX® N60K 35.0 100 magnesium stearate 3.5 1.0 Final: 350.0 100.0

6-tetrabenzazine (milled) was combined together with Mannitol powder, microcrystalline cellulose, PVP K29/32 and Tween 80 (Polysorbate 80) in a high shear granulator and initially dry mixed with a high speed paddle and grinder for 5 minutes. While mixing with a high paddle speed and a low grinder speed, purified water was added to the mixing powders to granulate the material. Further mixing and addition of water at high paddle speed and high chopper speed was continued until the desired granulation result was achieved. The resulting granulate was wet screened to break up any large agglomerates and this material was added to a fluidized bed dryer and dried at 60° C. until the desired LOD (Loss on Drying) was achieved. The dried material was screened through a #20 mesh sieve and the coarse material was ground to a particle size of less than 20 mesh. The dried and sized material was combined with sprayed mannitol and POLYOX® N60K in a diffusion mixer (V-Blender) where it was mixed for 15 minutes. The magnesium stearate was then passed through a 30 mesh screen and added to the blended material in the V-Blender. The contents were then plasticized for 3 minutes and discharged to compress the tablet. Using a rotary tablet press equipped with punches and dies of the desired shape and size, the plasticized mixture was compressed into tablets with a theoretical weight of 350 mg.

7.5 mg 6-tetrabenzazine gastroerosive sustained release (small tablet) (Formulation A). In table. 2 below discloses the elements of a tablet for a gastro-erosive granular composition with a total weight of 350 mg containing 7.5 mg of 6-tetrabenazine. The same process as described in example 1.

table 2

material mg/tab % d ₆ _ tetrabenzazine (crushed) 7.5 2.1 Mannitol Powder 191.0 54.6 Microcrystalline cellulose 63.7 18.2 PVP К29/32 14.0 4.0 Tween 80 (Polysorbate 80) 3, 8 eleven Mannogem EZ (spray dried mannitol) 31.5 9.0 POLYOX® N60K 35.0 100 magnesium stearate 3.5 10 Final: 350.0 100.0

mg d6-tetrabenzazine gastroretentive sustained release (large tablet) (Formulation B). In table. 3 below discloses the elements of a 700 mg gastroretentive tablet containing 15 mg of d6-tetrabenazine. The gastroretentive tablet is an elongated capsule measuring approximately 0.7087 inches long by 0.3071 inches wide, with rounded ends with a cup depth of 0.0540 inches on each opposite side.

- 15 042209

Table 3

Material mg/tab %_____ d ₆ - tetrabenzazine (crushed) 15.0 2.1 Mannitol Powder 357.5 51.1 Microcrystalline cellulose 119.0 17.0 PVP К29/32 26.0 3.7 Tween 80 (Polysorbate 80) 7.5 1.1 Mannogem EZ (mannitol, dried spray drying) 45.5 6, 5 POLYOX® N6 0K 122.5 17.5 magnesium stearate 7.0 10 Final: 700.0 100.0

7.5 mg 6-tetrabenzazine sustained release gastroretentive formulation (large tablet) (Formulation B). In table. 4 below discloses the elements of a 700 mg gastroretentive tablet containing 7.5 mg of n6-tetrabenazine. The gastroretentive tablet is an elongated capsule measuring approximately 0.7087 inches long by 0.3071 inches wide, with rounded ends with a cup depth of 0.0540 inches, on each opposite side. The same process as described in example 1. But the theoretical compression mass is 700 mg.

______________________Table 4__________________

Material mg/tab % d 6-tetrabenzazine (crushed) 7.5 1.1 Mannitol Powder 363.0 51.9 Microcrystalline cellulose 121.0 17.3 PVP К29/32 26.0 3.7 Tween 80 (Polysorbate 80) 7.5 eleven Mannogem® EZ (spray dried mannitol) 45.5 6, 5 POLYOX® N60K 122.5 17.5 magnesium stearate 7.0 1.0 Final: 700.0 100.0

mg 6-tetrabenazine immediate release tablet. In table. 5 below discloses the elements of a 125 mg total mass immediate release tablet containing 6 mg of n6-tetrabenazine.

Table 5

Material mg/tab % d b-tetrabenzazine (crushed) 6.0 4.8 Mannitol Powder 75.0 60.0 Microcrystalline cellulose 25.0 20.0 Sodium Starch Glycolate 2.5 2.0 PVP К29/32 6.0 4.8 Tween 80 (Polysorbate 80) 1.0 0.8 Mannogem® EZ (spray dried mannitol) 5, 8 4, 6 Sodium Starch Glycolate 2.5 2.0 magnesium stearate 1.2 1.0 Final: 125.0 100.0

6-tetrabenazine (milled) was combined together with mannitol powder, microcrystalline cellulose, sodium starch glycolate, PVP K29/32 and Tween 80 (Polysorbate 80) in a high shear granulator and initially dry blended with high paddle speed and high chopper speed within 5 min. While mixing with high paddle speed and low grinding speed, purified water was added to the mixing powders to granulate the material. Further mixing and addition of water at high paddle speed and high chopper speed was continued until the desired granulation result was achieved. The resulting granulate was wet screened to break up any large agglomerates and this material was added to a fluid bed dryer and dried at 60° C. until the desired LOD (Loss on Drying) was achieved. The dried material was screened through a #20 mesh sieve and the coarse material was ground to a particle size of less than 20 mesh. The dried and sized material was combined with spray dried mannitol and sodium starch glycolate.

In all methods and compositions described herein using deutetrabenazine, deutetrabenazine can be administered or formulated as part of a pharmaceutical composition as described in Table 1. 1-5 above.

Clinical Trials and First-HD Results

First-HD was a randomized, double-blind, placebo-controlled, parallel cohort study designed to evaluate the efficacy, safety, and tolerability of deutetrabenazine in patients with HD-associated chorea. This trial was conducted in the United States and Canada in collaboration with the Huntington Research Group.

Study plan

Subjects in First-HD were treated with deutetrabenazine or placebo starting at 6 mg once

- 16 042209 per day and titrated weekly to doses of 24 mg twice daily (total daily dose of 48 mg per day). A total of 90 objects (45 in each group) were included in the assessment over 13 weeks. Subjects were individually titrated to the optimal dose over a period of up to eight weeks, received maintenance therapy at the optimal dose for four weeks, and were taken off study drug in the last week of the trial.

Object distribution and demographic and background characteristics

Of the 90 randomized subjects, 87 completed the study. The study population was typical of subjects with chorea associated with HD. At the initial stage, the average age of the objects was 53.7 years. Most subjects were white (92.2%) and male (55.6%). The mean length of the CAG repeat among the subjects in the population was 43.9. At baseline, the mean TMS score was 12.7 in the entire population (range 8-19.5).

Study and Measurement Endpoints

The primary efficacy endpoint of the study was change from baseline to maintenance therapy (mean of Week 9 and Week 12) on the UHDRS Maximum Chorea Scale. The Overall Maximum Score, or TMS, is a clinician-based score for chorea in seven areas of the body: face, mouth/tongue, trunk, and four limbs, with higher scores representing more severe chorea. This is the same endpoint that was accepted by the FDA when it reviewed and approved tetrabenazine in 2008 (NDA 21894).

The UHDRS Total Mobility Assessment Scale (TMS) was defined as an additional performance endpoint in First-HD. TMS evaluates all motor features of HD, including features related to characteristic motor abnormalities other than chorea, such as dystonia, gait, parkinsonism, and postural instability.

The clinical significance of the change in TMS score was assessed using four predefined secondary endpoints that assessed changes from baseline to the end of treatment (Week 12). These secondary endpoints have been tested hierarchically:

1. Efficacy of treatment based on the patient's overall impression of the dynamics of the condition (PGIC);

2. Efficacy of treatment based on clinical global impression of progress (CGIC);

3. Scale of physical functioning SF-36 and

4. Equilibrium assessed using the Berg Equilibrium Test (BBT).

The PGIC and CGIC are single-item questionnaires that ask the subject and investigator, respectively, to rate the subject's general HD symptoms at specific visits after the start of therapy. Both scores use a 7-item Likert scale, with response scores ranging from very strong worsening (-3) to very strong improvement (+3) to assess overall response to therapy. Patients and clinicians were asked: Regarding your (or the subject's) general symptoms of Huntington's disease, how would you describe yourself (or the subject) compared to just before the start of the drug study. Treatment efficacy according to these scales was defined as a score of strong improvement or very strong improvement at week 12. Subjects who had no response at Week 12 were considered treatment failures.

Adverse events (AEs) and their potential relationship to treatment were also observed. The focus categories of AEs included those known to be associated with the use of tetrabenazine:

Psychiatric disorders: insomnia, depression/arousal depression, sleep disturbance, agitation, anxiety, suicidal thoughts, compulsions, impulsive behavior and sleep disorders;

Nervous system disorders: drowsiness, dizziness, akathisia/restlessness, cognitive impairment, salivation, dyskinesia, migraine, headache, loss of consciousness and syncope (fainting);

General disorders: irritability, fatigue, gait disturbance, chest pain and hangover; And

Gastrointestinal disorders: diarrhea, dry mouth, constipation, nausea, abdominal pain, dyspepsia, frequent bowel disturbances, gastrointestinal pain, vomiting, dysphagia, flatulence and salivary hypersecretion.

In addition to the AE reports, rating scales were used to monitor potential subclinical toxicity due to excessive monoamine depletion. Such safety rating scales have been used in the tetrabenazine development program. These scales used in First-HD included the Hospital Anxiety and Depression Scale (HADS), the Colombian Suicidal Seriousness Rating Scale (C-SSRS), the Swallowing Disorder Questionnaire (SDQ), the Unified Parkinson's Disease Rating Scale (Dysarthria Point) (UPDRS [ dysarthria]), the Barnes Akathisia Scale (BARS) and the Epworth Sleepiness Scale (ESS). In addition, UHDRS was performed at key visits, which includes cognitive, behavioral, and functional measures.

- 17 042209

The Swallowing Disorder Questionnaire (SDQ) was used prospectively to assess swallowing impairment during the study, as dysphagia is a common problem in patients with HD. This 15-item score has been validated in patients with Parkinson's disease and has been shown to be a sensitive and accurate tool for identifying patients with swallowing disorders arising from a variety of etiologies. The SDQ is recommended by the National Institute of Neurological Disorders and Stroke Common Data Elements for assessing swallowing impairment in Parkinson's disease, and is therefore also relevant to patients with HD, as they may have bradykinesia and other symptoms of parkinsonism as part of their disease.

During the study, slight fluctuations in vital signs (blood pressure, heart rate, respiratory rate and temperature) were observed.

results

The mean dose at the end of the treatment period was 39.7 mg (SD 9.3 mg, range 12-48 mg) in the deutetrabenazine group and 43.3 mg (7.6 mg, range 12-48 mg) in the placebo group. The mean dose for 10 subjects in the deutetrabenazine group with impaired CYP2D6 function (poor metabolizers or strong CYP2D6 inhibitory drugs) was 34.8 mg (3.8 mg, range 30-42 mg). The overall compliance rate was 94.1% and 95.1% for the placebo and deutetrabenazine groups, respectively.

Treatment with deutetrabenazine resulted in improvement in all endpoints and a reduction in the incidence of adverse events. In the results below, DTBZ=Deutetrabenazine, CI=confidence interval (based on t-distribution); SD=standard deviation; least squares and p-value were derived from a two-tailed treatment effect test and covariance model analysis with treatment duration and baseline covariate.

Chorea Overall Maximum Score (TMS). Treatment with deutetrabenazine resulted in a sustained improvement in the maximum chorea score. The TMC indicator at a given point in time is determined from paragraph 12 of the UHDRS. The change in TMS is the difference between baseline and maintenance therapy. Baseline is the average of screening and day 0, and maintenance is the average of week 9 and week 12. For the primary endpoint, subjects treated with deutetrabenazine achieved a significant reduction of 2.5 units in TMS from baseline before maintenance compared with placebo (p<0.0001). This reduction in maximum chorea was a 21 percentage point reduction compared to placebo (p<0.0001). Deutetrabenazine (DTBZ) was administered in an amount equal to approximately half the daily dose of tetrabenazine. Thus, the effectiveness of deutetrabenazine was achieved at about half the daily dose of tetrabenazine.

Table 6 Overall Chorea Maximal Chorea Rating Scale - Change from Baseline to ________________ Maintenance ________________

Change in the overall difference between the statistics of the maximum mean chorea score (DTBZ - placebo and

DTBZ Placebo ⁹⁵ % CI) ______________________(N=45)________(N=45)_______________________________ Absolute change in total chorea peak score (primary efficacy endpoint) |

Mean -4.4 (3.0) -1.9 (2.7) -2.5 (-3.7, -1.3) least squares (SD) p-value -- -- <0, 0001

Percent Change in Total Peak Chorea I (Additional Efficacy Endpoint) (%) |

Mean -37(25.7) -16(19.6) -21(-30.5, -11.1) least squares (SD) p-value ----<0.0001

General Motor Activity Scale (TMS)

In addition, a statistically significant improvement in TMS of 4 units was observed compared to placebo. The fact that the improvement in TMS was larger in magnitude than the improvement in TMS score (-2.5 units) suggests a benefit of treatment with deutetrabenazine for other HD motor symptoms in addition to reducing chorea. Much of this improvement was due to improvement in chorea, but overall maximal dystonia also contributed to this, with deutetrabenazine 0.9 (SE 0.24) points compared with placebo 0.1 (SE 0.32) points (p = 0 .02). From baseline to maintenance therapy, TMS improved by 37% in the deutetrabenazine groups versus 16% improvement in the placebo group (p<0.0001). Changes in other motor components of the UHDRS did not differ significantly between treatment groups, including no significant difference in changes in the parkinsonism subscale (finger tapping test, pronation/supination scores, stiffness, bradykinesia, gait, tandem walking, and pushing stability test) between deutetrabenazine and placebo groups.

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Table 7. Assessment of general motor activity - change from baseline to maintenance therapy

statistics DTBZ placebo difference between (N=45) (N=45) average (DTBZ - placebo) and 95% CI Least squares mean (SD) p-value -7.4 (6.3) -3.4 (5.5) -4.0 (-6.5, -1.5) 0.0023

Assessment of general motor activity: comparison with tetrabenazine.

In contrast, in a 12-week placebo-controlled study, tetrabenazine was shown to improve the UHDRS TMS score, but tetrabenazine treatment did not show a statistically significant improvement in the TMS score (Huntington Study Group, 2006). These results suggest that tetrabenazine controls HD-associated chorea, but patients may experience a possible decrease in motor function that offset the observed benefit for chorea.

Conclusion. Therefore, deutetrabenazine may represent an excellent choice for the treatment of movement disorders in general. Of note, deutetrabenazine was effective at about half the daily dose of tetrabenazine.

Patient Global Impression of Status (PGIC) and Clinical Global Impression of Status (CGIC). At the end of therapy, 51% (23 of 45) of patients treated with deutetrabenazine experienced strong improvement or very strong improvement based on PGIC, compared with 20% (9 of 45) of patients in the placebo group (p = 0.002). Similar results were found by treating physicians, where 42% (19 of 45) of patients treated with deutetrabenazine were assessed as having achieved the effect of treatment based on CGIC compared to 13% (6 of 45) of patients in the placebo group (p = 0.0022) . These results indicate that subjects treated with deutetrabenazine experienced a clinically significant benefit for their overall HD symptoms, and their treating physicians were also able to observe this benefit.

The improvement in these clinician and patient ratings demonstrates that the improvement measured by TMS and TMS translates into improvement in HD symptoms and further supports the clinical benefit of deutetrabenazine.

Table 8. Treatment effect at the end of therapy determined by PGIC and CGIC

Percent difference DTBZ placebo treatment effect (N=45) (N=45) (DTBZ - placebo) and (%) (%) 95% CI (%)

general impression of the patient about the dynamics of the condition: the effect of treatment at the end of therapy ^b

20 31 (12.4, 49.8) p-value s -- -- 0.0020 general clinical impression of the state dynamics: treatment effect at the end of therapy ⁵

13 29 (11.4, 46.4) p-value s_____--___________--__________0, 0022___________________

SF-36 physical functioning scale

The SF-36 Physical Functioning Scale was chosen as a key secondary endpoint because it is a patient reporting tool that has been used in many disease states and assesses physical activity related to patients living with HD. The 10-item Physical Functioning Assessment asks patients for information on self-care activities such as bathing, dressing, lifting or carrying groceries, climbing one or more flights of stairs, bending over, kneeling, walking 100 yards or more, and moderate and vigorous activity. The SF-36 Physical Functioning Scale has been shown to measure impairment experienced by people living with HD.

The mean change from baseline to week 12 on the SF-36 Physical Functioning Scale is shown below, where subjects treated with deutetrabenazine showed a mean improvement of 0.74 in treated patients from baseline compared to a deterioration of 3. 61 units in the placebo group (difference 4.3 units). In patients with more severe chorea at baseline (TMC > population median, or TMC > 12; n=49), the benefit of deutetrabenazine on physical functioning was greater, with a mean improvement of 7.1 units compared to placebo (p= 0.0075).

The change from baseline to week 12 on the SF-36 Physical Functioning Scale showed that subjects treated with SD-809 had improved physical functioning compared to patients treated with placebo (p=0.03). Analysis of SF36 by baseline chorea severity showed that SD-809 was more beneficial for subjects with more severe chorea (p=0.0075). Given that chorea can interfere with basic motor skills, gait and

- 19 042209 walking, it is not surprising that objects with more impaired function would benefit greatly from this measure.

Given the significant negative impact of chorea on patient quality of life and physical functioning, the statistically significant improvement in subjects' assessment of their ability to perform activities of daily living contributes to the clinical benefit of deutetrabenazine.

Table 9. SF-36 Physical Functioning Scale - Change from Baseline to Week 12

statistics Change in SF-36 score from baseline to week 12 DTBZ (Ν=45) Placebo (Ν=45) Difference mean placebo) between (DTBZ - and 95% CI N Average 45 0.74 43 -3, 61 4.34 (0, 41, 8.27) least squares value (SD) p-value (9, 773) (9,669) 0.0308

Berg balance test

The VVT is a 14-item equilibrium score that was used to assess whether a decrease in chorea affected balance, since many drugs currently used to treat chorea can worsen balance. IWT was evaluated as a measure of safety and an endpoint of efficacy. As summarized below, deutetrabenazine did not impair balance at the end of treatment and in fact the data numerically favored deutetrabenazine, although the improvement was not statistically significant (p=0.1415). In addition, there was no statistically significant difference between deutetrabenazine and placebo on VVT observed during the study.

Table 10 Change in Berg Equilibrium Scale from Baseline to Week 12

Change in IWT from baseline to week 12

statistics DTBZ (N=45) Placebo (N=45) Difference between mean (DTBZ - placebo) and 95% CI Average 2.2 1.3 1.0 (-0.3, 2.3) meaning (3.47) (4.04) least squares (SD) p-value -- -- 0.1415

Adverse events

Deutetrabenazine is generally well tolerated. Overall adverse event rates (AEs) were similar between the deutetrabenazine and placebo groups, with (60%) of subjects in each group experiencing at least one AE. There were no deaths in the study. There was one subject with two serious AEs (cholecystitis and irritable depression) in the deutetrabenazine group, and one subject with one serious AE (exacerbation of chronic obstructive pulmonary disease or COPD) in the placebo group. The same subject experiencing severe AEs in the deutetrabenazine group also reported suicidal ideation, which was not considered a serious AE, and subsequently withdrew from the study due to arousal AEs. In the placebo group, one subject reported suicidal ideation on the Colombian Suicidal Severity Scale, and one subject withdrew from the study due to atrial fibrillation AE. Evidence of good tolerability is further revealed by the same AE values leading to dose reduction, dose suspension and discontinuation. Finally, CYP2D6 genetic status did not affect dosing in this study or AE scores. As expected, slow metabolizers, either through genetics or concomitant medications, were dosed at somewhat lower levels and without additional AEs, supporting the notion that deutetrabenazine dosing can be clinically adjusted without relying on costly genotyping.

Table 11 Overview of treatment-related adverse events

DTBZ Placebo (N=45 (N=45)

Event type η (%) η (%)

Any treatment-related AE (TEAE) 27 (60.0)

Any mental disorder TEAE 8 (17.8)

Any disorders of the nervous system TEAE 8 (17.8)

Any serious TEAE 1 (2.2)

Any TEAE occurring with 3 (6.7) dose reductions

Any TEAE occurring with 1 (2.2) dose interruption

Any TEAE that resulted in withdrawal from 1 (2.2) (60.0) 8 (17.8) 10 (22.2) 1 (2.2) 3 (6.7) (2.2) (2 ,2) research

Similar rates of AE were also observed among the systems of the mental and nervous systems of the body, which are especially important for patients with HD. The number of objects reporting AE in some groups associated with the psyche of the nervous system, gastrointestinal and other general disorders is given in Table. 12 below. These body systems stand out because they include many of the main symptoms seen in patients with HD, as well as frequent AEs with tetrabenazine use. Subjects treated with deutetrabenazine had low rates of insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability and fatigue, and these rates were similar or weaker than in cases observed in subjects receiving placebo. Importantly, no parkinsonism or dysphagia was reported in the deutetrabenazine group. The most common AE observed in the deutetrabenazine group was drowsiness, which was observed in 11.1% of patients compared with 4.4% in the placebo group or with a difference between the drug and placebo of 6.7%.

Table 12 Adverse events resulting from treatment

System class Preferred DTBZ (N=45) placebo bodies term n(%) (N=45) n(%) PSYCHIATRIC Insomnia 1 (2.2) 0 DISEASES depression / agitiro 1 (2.2) 0 bathroom depression unusual 0 3 (6.7) dreams Agitation 0 1 (2.2) Anxiety 0 1 (2.2) suicidal idea 3 (6.7) 6 (13.3) Compulsion these 3 (6.7) 2 (4.4) impulsive 1 (2.2) 0 behavior sleep disorder 1 (2.2) 0 DISEASES Drowsiness 1 (2.2) 0 NERVOUS Dizziness 4 (8.9) 0 SYSTEMS Akathisia/Arousal 4 (8.9) 3 (6.7) other state cognitive 2 (4.4) 1 (2.2) disorders salivation 1 (2.2) 2 (4.4) dyskinesia 1 (2.2) 0 migraine 1 (2.2) 0 Headache 1 (2.2) 0 Loss of consciousness 1 (2.2) 0 Syncope 0 3 (6.7) ARE COMMON Irritability 0 1 (2.2) DISORDERS Fatigue 0 1 (2.2) Gait disturbance 0 1 (2.2) Chest pain 1 (2.2) 0 Hangover 1 (2.2) 0 GASTROINTESTINAL Diarrhea 0 3 (6.7) INTESTINAL Dry mouth 0 1 (2.2) DISEASES Constipation 0 1 (2.2) Nausea 3 (6.7) 6 (13.3) Pain in the upper 3 (6.7) 2 (4.4) parts of the abdomen Dyspepsia 1 (2.2) 0 Frequent movements 1 (2.2) 0 intestines Gastrointestinal 1 (2.2) 0 intestinal pain vomit 4 (8.9) 0 Dysphagia 4 (8.9) 3 (6.7) Flatulence 2 (4.4) 1 (2.2) hypersecretion 1 (2.2) 2 (4.4) saliva

Safety

In addition to AE reporting, rating scales were used to monitor potential subclinical toxicity due to excessive monoamine depletion. Such safety scales were used in the tetrabenazine development program. These scales used in First-HD included the Hospital Anxiety and Depression Scale (HADS), the Colombian Suicidal Seriousness Rating Scale (C-SSRS), the Swallowing Disorder Questionnaire (SDQ), the Unified Parkinson's Disease Rating Scale (Dysarthria Point) (UPDRS [ dysarthria]), the Barnes Akathisia Scale (BARS) and the Epworth Sleepiness Scale (ESS). In addition, UHDRS was performed at key visits, which includes cognitive, behavioral, and functional measures.

These safety scales showed that deutetrabenazine did not cause depression, anxiety, suicidality, akathisia, drowsiness, or difficulty speaking, as the difference between groups on the scales was small and not clinically significant. In fact, swallowing function, which is an important cause of morbidity and mortality in patients with HD, was significantly improved in patients treated with deutetrabenazine compared with placebo, and this was consistent with the improvement observed for motor function. The clinical significance of this improvement is described below.

- 21 042209

Swallowing disorder

The Swallowing Disorder Questionnaire (SDQ) was used prospectively to assess swallowing impairment during the study, as dysphagia is a common problem in patients with HD. This 15-item score has been validated in patients with Parkinson's disease and has been shown to be a sensitive and accurate tool for identifying patients with swallowing disorders arising from various etiologies. The SDQ is recommended by the National Institute of Neurological Disorders and Stroke Common Data Elements for assessing swallowing impairment in Parkinson's disease, and is therefore also relevant to patients with HD, as they may have bradykinesia and other symptoms of parkinsonism as part of their disease. In FIG. 2 shows the mean change from baseline in SDQ over time, demonstrating a significant improvement in swallowing with deutetrabenazine treatment compared with placebo.

Additional UHDRS estimates

The UHDRS rating scale was used throughout the FirstHD study to monitor safety. The UHDRS Parkinsonism subscale score (Part I) showed no evidence of parkinsonism in subjects treated with deutetrabenazine or placebo, consistent with the absence of AE as extrapyramidal symptoms. These results were further supported by the absence of significant changes in both treatment groups regarding UPDRS dysarthria.

The results of the UHDRS Cognitive Assessment (Part II) also showed no significant change from baseline or consistent trends between treatment groups, indicating no cognitive decline with treatment.

The UHDRS Behavioral Assessment (Part III) demonstrated an improvement in mean global behavioral score for subjects treated with deutetrabenazine compared to the placebo group, however the difference did not reach statistical significance. Importantly, there was no worsening of depressed mood, apathy, self-esteem, irritability, aggressive behavior, suicidal thoughts, hallucinations, or delusions. The improvement in overall score was due to differences in anxiety and compulsive behavior (FIG. 4 AC).

The UHDRS Functional Rating Scales (Part IV), the Independence Rating Scales (Part V), and the Overall Functional Ability Rating Scale (Part VI), which were assessed at baseline and again at week 12, showed no clinically meaningful change from baseline in either group treatment or differences between treatment groups.

During the study, minor fluctuations in vital signs (blood pressure, heart rate, respiratory rate and temperature) were observed; these changes were generally similar between the deutetrabenazine and placebo treatment groups and were not assessed as clinically significant. No consistency was observed between group differences. In addition, there was no evidence that hypotension, dizziness or orthostasis was associated with treatment with deutetrabenazine.

Body mass

Compared with the placebo group, treatment with deutetrabenazine resulted in a mean weight gain of approximately 2.1 kg compared to placebo (at week 12 mean (SD) change in body weight +1.8 (3.4) kg for deutetrabenazine vs -0.30 (2.5) kg in the placebo group (treatment effect + 2.1 kg) Weight gain correlates with improved treatment and health outcomes in patients with chorea and may lead to a partial reduction in chorea (while improved swallowing may lead to better food intake , which, when combined with less caloric energy intake, which is due to a decrease in pathological involuntary movements, can lead to weight gain), in addition to improved function or behavioral symptoms such as anxiety, which can suppress appetite.

Adverse events and safety: comparison with tetrabenazine

The variable pharmacokinetics of tetrabenazine may affect its tolerability and limit its clinical use. The half-life of the circulating active metabolites, α- and β-dihydrotetrabenazine, is short. These short half-lives require frequent dosing and result in large fluctuations in plasma concentrations. The high peak concentrations and variability in plasma levels associated with tetrabenazine may contribute to the poor tolerability that is often observed.

Accordingly, tetrabenazine's prescribing information contains several warnings about side effects and potential safety issues:

The highlighted warning indicates that tetrabenazine increases the risk of depression and suicidal thoughts and behaviors (suicidality) in patients with HD.

Higher rates of treatment-related adverse events were observed in patients treated with tetrabenazine compared with patients treated with placebo, including drowsiness/sedation, insomnia, depression, akathisia, anxiety, and fatigue (see Table # below Error ! Link to source not found).

Dose escalation was discontinued or study drug dose was reduced due to adverse events in 52% (28 of 54) of patients randomized to receive tetrabenazine.

In a 12-week randomized controlled trial of tetrabenazine, adverse events indicative of parkinsonism (eg, parkinsonism, bradykinesia, hypertension, rigidity) were observed in 15% of patients using tetrabenazine compared with 0% of patients using placebo.

Prevention and prevention leads to the risk of dysphagia underlying the symptom of HD and the known side effect of decreased dopaminergic neurotransmission. Although a low grade of dysphagia was reported in the 12-week study, in open studies dysphagia was observed in 8-10% of patients treated with tetrabenazine, including some cases associated with aspiration pneumonia. It is not clear if these cases are related to treatment, however the FDA has expressed concern that dysphagia events, which can have devastating clinical consequences, may be significantly underestimated in tetrabenazine's NDA. Of note, in a retrospective study of 98 patients treated with tetrabenazine for hyperkinetic movement disorders, dysphagia was observed in 19% of patients.

At 50 mg, tetrabenazine caused a mean increase in the QTc interval of approximately 8 ms (90% two-sided confidence interval [CI]: 5, 10.4 ms).

The safety profile of tetrabenazine observed in a 12-week controlled study is reflected in the instructions for use, as described below.

Table 13 Treatment-related adverse reactions in patients treated with tetrabenzazine occurred at a higher frequency than placebo in a 12-week, double-blind, placebo-controlled trial of tetrabenzazine

BODY SYSTEM Preferred Tetrabenazine placeb term (N=54) O n(%) (N = 30) η (%) PSYCHIATRIC Sedation/drowsiness 17 (31) 1 (3) DISORDERS Insomnia 12 (22) 0 Depression 10 (19) 0 Anxiety/increased anxiety 8 (15) 1 (3) Irritability 5(9) 1 (3) Decreased appetite 2(4) 0 obsessive reaction 2(4) 0 CENTRAL AND Akathisia 10 (19) 0 PERIPHERAL Retention issues 5(9) 0 NERVOUS SYSTEM equilibrium parkinsonism/bradykin 5(9) 0 ezia Dizziness 2(4) 0 dysarthria 2(4) 0 Unsteady gait 2(4) 0 Headache 2(4) 1 (3) DISORDERS Nausea 7 (13) 2 (7) GASTROINTESTINAL INTESTINAL SYSTEM Vomit 3 (6) 1 (3) ORGANISM IN GENERAL Fatigue 12 (22) 4 (13) A fall 8 (15) 4 (13) ARE COMMON Scalped wound (head) 3 (b) 0 ecchymosis 3 (6) 0 DISEASES Upper infection b (11) 2 (7) RESPIRATORY respiratory tract SYSTEMS Confused breath 2(4) 0 Bronchitis 2(4) 0 DISORDERS disorder 2(4) 0 URINARY SYSTEM urination

Compared to deutetrabenazine, tetrabenazine appears to cause more side effects.

ARC HD

In the second clinical trial, a method was used to switch patients with adequate control of chorea using tetrabenazine to treatment with deutetrabenazine. Alternative for Chorea Reduction in Huntington's Disease (ARC-HD) was an open-label, non-comparative study in which subjects with overt HD who received FDA-approved doses of tetrabenazine for the treatment of chorea or successfully completed First-HD were invited to participate.

Thus, the study consisted of two cohorts. An additional cohort (75 subjects) successfully completed the First-HD study described above, including a one-week washout; A switching cohort (37 subjects) switched overnight from stable dosing (>8 weeks) tetrabenazine to deutetrabenazine in a switching method designed to achieve comparative systemic exposure to total α and β metabolites. Other key study inclusion criteria included: a diagnosis of overt HD as evidenced by characteristic features

- 23 042209 motility during the examination; documented extended repeat cytosine adenine guanine (CAG) (>37) and overall functional ability (TFC) score >5 at or before screening; the ability to walk unaided for at least 20 yards (assistive devices such as walkers or canes are acceptable); and the subject has a trusted guardian who interacts with the subject on a daily basis, oversees study drug administration, ensures attendance at study visits, and participates in evaluations as needed. Key exclusion criteria included severe untreated or prior psychiatric illness (eg, depression) at screening or at baseline; taking concomitant dopamine receptor antagonists, dopamine agonists, levodopa, reserpine, N-methyl-D-aspartate receptor antagonists, or monoamine oxidase inhibitors within 30 days of screening or baseline; and a score of >11 on the Hospital Anxiety and Depression Scale (HADS) Depression Subscale, a score of >11 on the Swallowing Disorder Questionnaire (SDQ), or the Unified Parkinson's Disease Rating Scale (UPDRS) score of >3 for dysarthria at screening or at baseline.

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

Study plan

Guidelines for investigators on switching subjects from stable doses of tetrabenazine to deutetrabenazine in the Switch ARC-HD study were developed to minimize the risk that a dose switch would result in a loss of efficacy or an increase in adverse events. The transition method used was based on modeling and simulation of Phase 1 pharmacokinetic data for deutetrabenazine and tetrabenazine. The aim of the pharmacokinetic analysis was to identify an initial dosing regimen of deutetrabenazine that is predicted to provide steady state exposure to the active a and β metabolites and that is less than or equal to the predicted steady state AUC of the active alpha and beta metabolites of tetrabenazine. but with a lower Cmax.

In a Phase 1, single-centre, open-label, cross-over clinical trial, each of 24 healthy subjects received single doses of 25 mg tetrabenazine and 15 mg deutetrabenazine. One of the objectives of the clinical trial was to evaluate and compare the safety of deutetrabenazine versus tetrabenazine.

Subjects in the switching cohort completed a full screening evaluation. Subjects who were eligible for the study were subsequently switched from a tetrabenazine dose regimen to a deutetrabenazine regimen that was predicted to be comparable to the current tetrabenazine regimen. Subjects took tetrabenazine on their existing schedule during the night of day 0 and switched to their assigned deutetrabenazine regimen the next morning (Study Day 1). The starting dose was based on a transition method determined by a phase 1 pharmacokinetic comparison of deutetrabenazine and tetrabenazine, assuming that the starting dose of deutetrabenazine is approximately 50% of the existing dose of tetrabenazine (Table 15). After the first week of treatment, the dose of deutetrabenazine was allowed to be adjusted up or down once a week in increments of 6 mg/day until a dose that adequately controlled chorea was identified, a protocol was established for the subject to determine a clinically significant adverse event or maximum tolerated dose. . The investigator, in consultation with the subject and caregiver, determined when an adequate level of chorea control had been achieved. If a subject experienced a clinically significant deutetrabenazine-related adverse event, the investigator determined whether dose reduction or discontinuation was required.

Table 15 Method for switching patients from tetrabenazine to deutetrabenazine

Incoming total daily dose of tetrabenazine a Starting total daily dose of deutetrabenazine Initial total daily deutetrabenazine regimen Follow-up regimen of deutetrabenase on morning dose Evening dose 12.5 mg 6 mg 6 mg Tsosa adjusted up or down (increment of 6 mg/day once a week) to achieve a dose that adequately controls chorea 2 5 mg 12 mg 6 mg 6 mg 37.5 mg 18 mg 9 mg 9 mg 50 mg 2 4 mg 12 mg 12 mg 62.5 mg 3 0 mg 15 mg 15 mg 7 5 mg 3 6 mg 18 mg 18 mg 87.5 mg 42 mg 21 mg 21 mg 100 mg 4 8 mg 2 4 mg 24

Subjects in the additional cohort completed a 1-week washout in First-HD custody, during which the mean TMS score returned to baseline. The dose of deutetrabenazine for these subjects was titrated from an initial dose of 6 mg per day to a dose that controlled chorea and

- 24 042209 was well tolerated.

For both cohorts, 6, 9, and 12 mg oral tablets were used. Doses of 12 mg and above were administered in two divided doses approximately 10 hours apart. All study regimens were administered orally with meals. The maximum total daily dose of deutetrabenazine was set at 72 mg per day, unless the subject was receiving a strong inhibitor of CYP2D6 (eg paroxetine) in which case the maximum total daily dose was 36 mg.

The subjects were present at regular clinic visits to assess safety and establish the optimal dose. The investigator, in consultation with the subject and caregiver, determined when an adequate level of chorea control had been achieved; the dose of DTBZ could be increased weekly until there was adequate control of chorea, a protocol was established in the subject to determine the clinically significant adverse event or the maximum tolerable dose. In long-term treatment, all patients had constant contact with the study site to assess the safety and control of chorea. Long-term treatment will continue until deutetrabenazine becomes commercially available in the US

A total of 37 subjects with HD-related chorea that was adequately controlled by tetrabenazine who were switched from tetrabenazine to deutetrabenazine in the ARC-HD Switch were included in the analysis to assess maintenance of chorea control after switching to another drug. Each of the subjects included in the analysis was switched from tetrabenazine treatment to a daily dose of deutetrabenazine, which was administered twice a day, which was approximately 30-50% of their previous total daily dose of tetrabenazine.

results

Dose and effectiveness.

Given differences in prior therapy and expected changes in chorea control after initiation of deutetrabenazine therapy in the two cohorts, efficacy data were summarized separately for the two groups. Data from the two cohorts are shown below through week 15. As this study is ongoing, data from subsequent weeks is still being collected and analyzed, and the results include too few patients to draw meaningful conclusions at this stage.

Dose - Switch cohort.

The mean dose of TBZ at baseline was 42 mg, and after night switching, the mean dose of deutetrabenazine was 20 mg. The mean daily doses of deutetrabenazine after switching from TBZ are shown in Table 1 below. 15.

Table 15 Baseline TBZ Dose and DTBZ Dose Conversion and Titration

statistics TBZ dose at baseline (mg) Daily dose of DTBZ (mg) Week 8 Week 15 Day 1 - Week 1 Week 4 N 37 37 36 22 15 Medium 42, 1 20.3 29, 7 33.5 36, 0 dose (SD) (19.58) (10.23) (10.44) (11.36) (14 .70) Minimum, Maximum 12.5, 100 6, 48 12, 48 12, 48 12, 60

Dose - Additional cohort.

Average daily doses of deutetrabenazine after washout and initial doses of 6 mg/day are shown in Table 1 below. 16.

Table 16 Titration of the daily dose of DTBZ

statistics Daily dose of DTBZ (mg) Week 2 Week 4 Week 8 Week 15 N 62 56 44 34 Average dose 11.8 24.2 38.9 41, 1 (SD) (1.07) (4.57) (11.09) (9.24) Minimum, 6, 12 6, 36 6, 48 18, 48 Maximum

Overall Maximal Chorea (TMS) Rating Scale - Switching Cohort.

One week after switching to deutetrabenazine, while subjects were still receiving their initial total daily dose of deutetrabenazine, the mean score for total chorea decreased approximately one point from baseline (mean change ± standard error [SE] from baseline was 0.72 ± 2,6), indicating that deutetrabenazine retained control of chorea in these subjects. A subset of 35 subjects were also assessed for chorea four weeks after switching to deutetrabenazine. In this set of subjects, the mean (±SE) change from baseline was 0.7±3.0 at week 4, providing further demonstration of maintenance of chorea control. In addition, data for 21 patients were available at week 8; these data demonstrated a change from baseline of -1.9±3.5 units on the TMS scale; at week 15, -1.2 ± 4.1 units. The results are shown below in table. 17. A summary of the change in observed mean chorea score and the mean daily dose of tetrabenazine or deutetrabenazine corresponding to the chorea score is shown in

- 25 042209 fig. 6.

Table 17 Estimated total maximal chorea (switch cohort)

Total maximum chorea score Mean (SD) change from

Moment of time N Mean value (SD) N baseline p - value ^{of a} original 37 12.47 (5, 26) -- -- -- level Week 1 37 11.76 (5.11) 37 -0.72 (2.59) 0.1007 Week 4 36 11.86 (5.23) 36 -0.74 (3.01) 0.1507 Week 8 21 10.10 (5.56) 21 -1.86 (3.52) 0.0252 A week 15 10.87 (5.99) 15 -1.17 (4.07) 0.2850 15

Total maximal chorea (TMS) - additional (Rollover) cohort.

At week 2, a statistically significant mean (SD) decrease from baseline by

1.9 (3.0) units (p<0.0001). This effect persisted through week 15, when the mean (SD) reduction from baseline was 4.5 (5.0) units (p=0.0001). These results are consistent with those obtained for DTBZ in First-HD. The results are shown below in table. 18.

Table 18 Estimated total maximal chorea (additional cohort)

Total maximum chorea score

Moment of time N Average (SD) meaning N Mean (SD) change from baseline p - value ^{of a} Baseline 71 12.0 (4 .25) -- -- -- Week 2 61 10.1 (3 .41) 58 -1.9 (2.95) <0.0001 Week 4 55 9.8 (3, 69) 52 -2.5 (3.21) <0.0001 Week 8 43 7.9 (3, 91) 40 -4.5 (3.34) <0.0001 Week 15 34 7.9 (4, 05) 33 -4.5 (4.04) <0.0001

Total locomotor activity score (TMS) - switching cohort.

In addition, general motor symptoms as measured by TMS were maintained after dose conversion and appeared to improve at week 8 as shown by mean (SD) change from baseline in TMS -3.7 (7.8). The results are shown below in table. 19.

Table 19 Estimated total locomotor activity over time (switch cohort)

General indicator of physical activity

Moment of time N Mean value (SD) N Average (SD) change from baseline R- value a initial 37 38.49 (18, 679) - - - level 1 Week 37 36.35 (18.043) 37 -2.14 (5.414) 0.0218 4 week 36 37.14 (19.516) 36 -1.85 (8.419) 0.1966 8 week 24 34.58 (18.268) 24 -3.73 (7.787) 0.0279 15 15 35.00 (22.984) 15 -1.93 (10.910) 0.5037 a week

A summary of the change in observed mean chorea score, and mean daily dose of tetrabenazine or deutetrabenazine corresponding to chorea score, are shown in FIG. 7.

Total locomotor activity score (TMS) - additional cohort.

A statistically significant mean decrease in TMS from baseline was observed as early as week 2 (3.9 units, p<0.0001) and was maintained until week 15 (8.0 units, p=0.0001). The results are shown below in table. 20.

Table 20 Estimation of general motor activity (additional cohort)

General indicator of physical activity

Moment of time N Mean value (SD) N Mean (SD) change from baseline p - value ^{of a} initial 71 35, 3 (16, 34) -- -- -- level 2 weeks 61 32.4 (15.23) 58 -3.9 (6.67) <0.0001 4 week 55 32, 1 (16, 84) 52 -5.9 (7.88) <0.0001 8 week 43 31.0 (18.07) 40 -8.3 (8.58) <0.0001 15 35 30.5 (17.70) 33 -8.0 (8.41) <0.0001

a week

The fact that the mean improvement in TMS ((-3.7 units at week 8 in the switch cohort and -8 units at week 15 in the add-on cohort) was greater in magnitude than the mean improvement in TMS score (-1 .9 units at week 8 in the switch cohort and -4.5 units at week 15 in the add-on cohort) suggests a benefit of DTBZ treatment for other HD motor symptoms in addition to reduction in chorea.

- 26 042209

Other deuterium-substituted tetrabenazines and valbenazines are expected to be effective in the treatment of chorea and other symptoms associated with Huntington's disease and other movement disorders and pathological involuntary movements in general.

Adverse events

DTBZ is generally well tolerated and the safety results in both supplementary and switch cohorts are consistent with the safety profile observed in First-HD.

In the additional cohort, 39 (52.0%) subjects experienced AE, with AEs rated as mild or moderate in intensity in 36 (92.3%) of these 39 subjects. The most common AEs in the additional cohort were falling (10 subjects, [13%]), drowsiness (6 [8%]), depression (6 [8%]), and insomnia (6 [8%]). A similar percentage of subjects in the additional cohort experienced AE from weeks 1 to 8 (45.3%) compared to week 8 prior to the data collection end date visit (43.2%). Five subjects had AEs that resulted in dose reduction or dose suspension. Three subjects experienced severe AEs (anxiety, major depression, suicidal ideation, dehydration, encephalopathy, and suicidal depression), with one of these severe AEs (major depression) leading to withdrawal from the study. Three additional subjects withdrew from the study due to AE (worse chorea, suicidal ideation and depression).

In the switching cohort, 21 (56.8%) subjects experienced at least one AE, with AEs rated mild to moderate in intensity for 20 (95.2%) of 21 patients. The most common AEs in the switching cohort were drowsiness (9 subjects [24%]), anxiety (3[8%]), and falling (3[8%]). Most of these common events occurred within the first 8 weeks of the study (22 subjects in the switch cohort reached week 8 by the end of data collection visit). The most common AEs occurred with similar rates from day 1 through week 1, from week 2 through week 4, and from week 5 through week 8. There were no adverse events of chorea or worsening of chorea during the reporting period, including in the first week after switching from tetrabenazine to deutetrabenazine. Two subjects experienced severe AEs (pneumonia and dehydration), no subjects withdrew from the study due to AEs, and four subjects had an AE that resulted in a dose reduction or dose suspension.

There was no apparent increase in the overall prevalence of AE in patients with impaired CYP2D6 metabolism (including subjects using a strong CYP2D6 inhibitor and weak CYP2D6 metabolizers).

Frequently occurring AEs during treatment, defined as events occurring in at least 4% of subjects at all times in any cohort, are summarized in Table 1 below. 21. The most common AEs during the entire treatment period in the additional cohort were reduced (10 subjects, [13.3%]), somnolence (6 [8.0%]), depression (8 [10.7%]), and insomnia (6 [8.0%]). The most common AEs during the entire treatment period in the switching cohort were carrion (3 subjects, [8.1%]), drowsiness (9 [24.3%] but most were transient and did not require dose adjustment), depression (8 [10.7%]) and anxiety (3[8.1%]). The types of common adverse events observed were consistent with those observed with deutetrabenazine treatment in First-HD. Falls are difficult to assess in this study population with chorea and HD; most of the falls were not thought to be study drug related.

Table 21. TEAE found in at least 4% of subjects in any cohort

Additional Cohort

Event cohort (N=75) n (%) switching (N=37) n(%) A fall 10 (13.3) 3 (8.1) depression a 8 (10.7) 2 (5.4) Drowsiness 6 (8.0) 9 (24.3) Insomnia 6 (8.0) 1 (2.7) Diarrhea 4 (5.3) 2 (5.4) anxiety 3 (4.0) 3 (8.1) Constipation 3 (4.0) 2 (5.4) Dry mouth 3 (4.0) 2 (5.4) Irritability 3 (4.0) 2 (5.4) Vomit 3 (4.0) 1 (2.7) Fatigue 3 (4.0) 1 (2.7) sleep disorder 3 (4.0) 0 nasopharyngitis 2 (2.7) 2 (5.4) Disorientation 0 2 (5.4)

Additional security indicators

Safety scales were included in the study design to monitor subclinical toxicity associated with deuterabenazine treatment. These included observed values and changes in the UHDRS, SDQ, the UPDRS Dysarthria Inventory, the Barnes Akathisia Rating Scale (BARS), HADS, the Epworth Sleepiness Scale (ESS), the Colombian Suicidal Severity Rating Scale (C-SSRS), and the Montreal Cognitive Assessment ( MoCA©). Overall safety scale analysis showed no increased risk of treatment with deutetrabenazine until week 28, corresponding to the end date of data collection.

- 27 042209 for this study. Eight patients from the additional cohort had a clear decrease in two of the four cognitive measures (MoCA and verbal fluency task) at week 28. These changes were often associated with AE (eg, drowsiness, fatigue, urinary tract infection) and were generally not associated with decreased efficacy of functional measures. No clinically significant changes in vital signs, ECG, or clinical laboratory evaluations were observed during the course of the study. In terms of body weight, from baseline to week 15, body weight increased in the supplementary cohort and changed minimally in the switch cohort. After week 15, there was a trend towards weight loss at week 28 in both cohorts (additional cohort, 1.4 kg, switching cohort, 1.9 kg), however, the decrease in the number of subjects reaching the week 28 milestone limits the interpretation of these results.

Taken together, the results of this study support the efficacy of deutetrabenazine as an effective therapeutic option with a favorable safety profile for the treatment of HD-associated chorea. These results support the safety of overnight switching from TBZ to a predictive AUC-matched dose of deuterabenazine, which can be achieved without loss of chorea control.

Tardive dyskinesia

An open, non-comparative study in male and female subjects with moderate to severe drug-induced tardive dyskinesia (TD) was conducted to evaluate the safety and tolerability of long-term maintenance therapy with deutetrabenazine and to evaluate the effectiveness of long-term maintenance therapy with deutetrabenazine in reducing the severity of pathological involuntary events. TD movements.

Study plan

Inclusion criteria included: age at least 18 years old; successful completion of a previous controlled trial of moderate to severe deutetrabenazine TD; history of use of a dopamine receptor antagonist for at least 3 months (or 1 month in subjects 60 years of age or older); clinical diagnosis of TD and symptoms for at least 3 months; for objects with existing mental illnesses:

psychiatrically stable and no change in psychoactive drug use within 30 days prior to screening (45 days for antidepressants);

subjects on long-acting (depot) drugs have been on stable therapy (dose, frequency) for >3 months prior to screening and the subject has a psychiatrist who is aware of the subject's participation in the trial and does not expect any changes in the subject's treatment regimen (drug, dose, frequency) within the next 3 months;

history of compliance with prescribed medications; the ability to swallow the study drug whole; lives in a stable environment and has appropriate supervision to follow all study procedures, attend all study visits, and participate safely in the trial; sufficient reading skills to comprehend the rating scales filled in by objects; Women of childbearing potential agree to use one of the following acceptable methods of contraception from screening to completion of the study if they are sexually active:

IUD or intrauterine system for at least 3 months prior to screening;

a subject or partner using a barrier method with spermicide during the screening period until completion of the study;

partner has a documented vasectomy > 6 months prior to enrollment; or stable hormonal contraception (with an approved oral, transdermal, or depo regimen) for at least 3 months prior to screening.

Exclusion criteria included: subject received tetrabenazine within 7 days of study entry, or any of the following drugs within 30 days of study entry: reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of study entry) and drugs with strong anticholinergic activity (trihexyphenidyl, benztropine, orphenadrine, procyclidine and biperiden), metoclopramide, promethazine, prochlorperazine, stimulants (i.e. methylphenidate, amphetamine/dextroamphetamine, lisdexamphetamine, etc.), monoamine oxidase inhibitors and (MAOI ), levodopa or dopamine agonists; the subject has a neurological condition other than TD, which may interfere with the assessment of the severity of dyskinesias; serious untreated or past psychiatric illness at the start of the study; active suicidal ideation at the start of the study; history of any of the following within 6 months of study entry: previous intent to act on suicidal intent with a specific plan (yes to C-SSRS question 5), regardless of level of ambivalence during suicidal ideation, previous preparatory acts of a suicidal nature, or suicidal behavior or a previous actual, aborted or aborted suicide attempt;

- 28 042209 score >11 on the Hospital Anxiety and Depression Scale (HADS) depression subscale at baseline; the subject is disabled or has signs of dementia; the subject has unstable or serious medical illness at the time of the start of the study; history (within 3 months) or presence of aggressive behavior; QTcF value > 450 ms (men) or > 460 ms (women) or > 480 ms (with right bundle branch block [RBBB]) on a 12-lead electrocardiogram (ECG) at baseline; Evidence of liver failure at screening as determined by: aspartate transaminase (AST) or alanine aminotransferase (ALT) > 2.5 times upper limit of normal (ULN), alkaline phosphatase (ALP), or total bilirubin (TBil) > a 2 times the ULN (but subjects with Gilbert's Syndrome are eligible if approved by the Medical Review, and subjects with abnormalities in two or more of these analytes (AST, ALT, ALP, TBil) must be approved by the Medical Review to be included), and prothrombin time is prolonged > 4 s; positive hepatitis B surface antigen (HBsAg); evidence of significant impairment of renal function at screening, identified by creatinine clearance <50 ml/min, as estimated by the Cockcroft-Gault formula; known allergy to tetrabenazine or to any of the components of deutetrabenazine; participated in a drug or device investigational study (excluding a study used to treat deutetrabenazine) and received an investigational drug within 30 days (or 5 drug half-lives) of study entry, whichever is longer ; the subject is pregnant or breastfeeding at the start of the study; and are currently using illegal drugs at the start of the study.

Dosing scheme. Deutetrabenazine tablets were presented in doses of 6, 9, 12, 15 and 18 mg. During dose adjustment/titration, deutetrabenazine was supplied in blister packs for a week. During long-term treatment, deutetrabenazine will be supplied in containers of 30 units. The study drug was administered as follows. All treatments were administered twice daily (BID) with food, approximately 10 hours apart throughout the day. The starting dose was deutetrabenazine 12 mg/day (6 mg BID) regardless of previous treatment in the original study. Evaluation of previous treatment from the original study remained blinded. The maximum total daily dose of deutetrabenazine was 48 mg/day (24 mg BID), except when the subject was on a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion), in which case the maximum total daily dose is 36 mg/day. Daily doses up to 36 mg/day were administered as one BID tablet, while daily doses of 42 mg/day and 48 mg/day were administered as two BID tablets. During the titration period, the dose of deutetrabenazine should be increased weekly in increments of 6 mg daily until 1) there is adequate control of dyskinesia; 2) the subject will not experience a protocol-defined clinically significant AE (defined as related to the investigational medicinal product, and either a) moderate or severe in intensity, or b) meets SAE criteria); or 3) the maximum tolerated dose will be reached. If the subject experienced a clinically significant AE related to deutetrabenazine, then the investigator determined whether a dose reduction or dose suspension was required.

Long term treatment

For all subjects participating in the long-term treatment period, the dose of deutetrabenazine can be adjusted (up or down) in increments of 6 mg per day, if necessary, to optimize the control of dyskinesia while minimizing AE. However, such dose changes can occur no more than once a week.

Titration period (up to 6 weeks).

Subjects who successfully completed the original study were eligible for this study after a 1-week washout period and final evaluation. Because the subjects discontinued the study drug or placebo within 1 week, they were titrated to the dose of deutetrabenazine in this study. During titration, the investigator, in consultation with the subject, determined when an adequate level of dyskinesia control had been achieved. The dose of deutetrabenazine was adjusted (up or down) in increments of 6 mg per day up to once a week until adequate control of dyskinesia, a clinically significant adverse event associated with study drug, was achieved (either a) moderate or severe. intensity, or b) a serious adverse event), or have reached the maximum tolerated dose. If the subject experienced a clinically significant AE related to deutetrabenazine, then the investigator determined whether dose reduction or suspension was necessary. Subjects had a telephone contact at week 1 and a clinic visit at week 2 to assess safety and establish a study drug dose that adequately controlled dyskinesia and was well tolerated. Although subjects entered the long-term treatment period after week 2, titration continued until week 6 to optimize dose.

Long-term treatment period (up to 52 weeks).

During long-term treatment, subjects will continue to be titrated up to week 6. During

- 29 042209 of this period, all subjects will be contacted by phone at week 3 (first week of the long-term treatment period) and week 5 and will return to the clinic at weeks 4, 6, 15, 28, 41 and 54 for safety assessment and control of dyskinesia. Subjects who have not reached a dose level that adequately controls dyskinesia and is well tolerated by the time of the week 6 visit should have ad hoc visits or telephone contacts to further adjust their dose up or down. Interaction with the clinical facility for dose adjustments should alternate between telephone contacts and clinic visits. In long-term treatment, additional dose adjustments of deutetrabenazine may be made if necessary, but not more than once a week, and only in increments of 6 mg per day. Dose adjustment should be based on all available information, including subject and caregiver reports (if applicable) of AE and dyskinesia control, and information from rating scales and safety ratings when available.

Safety follow-up after treatment

All subjects will discontinue study drug at the week 54 visit and return for their final clinic visit at week 55 for safety assessment, control of dyskinesia, and motor function. During this 1-week washout period, subjects must not take prohibited concomitant medications. Subjects will also have a follow-up telephone contact at week 58, four weeks after the last dose of study drug, to evaluate AE and concomitant drug use.

Final Criteria for Safety Evaluation

Safety and tolerability will be assessed throughout the study by monitoring the following parameters: adverse events (AEs), clinical laboratory tests, physical examination, vital signs, 12-lead ECG, Unified Parkinson's Disease Rating Scale (UPDRS)6 Part III (Motor Examination) ), the Barnes Akathisia Rating Scale (BARS), the Hospital Anxiety and Depression Rating Scale (HADS), the Columbia Suicidal Intention Severity Scale (C-SSRS), the Epworth Sleepiness Scale (ESS), and the Montreal Cognitive Assessment (MoCA©).

Criteria for the final evaluation of effectiveness

The following metrics have been or will be used to evaluate efficacy: change in the Pathological Involuntary Movement Rating Scale (AIMS) (items 1-7) from the start of the study to the end of long-term therapy (week 54), which was assessed using a blind centralized video assessment; the proportion of subjects that achieved treatment effect at the end of long-term therapy (week 54), based on clinical global impression of change (CGIC) (in which treatment effect is defined as strong improvement or very strong improvement); change in modified cranial and cervical dystonia score (CDQ-24) from study entry to end of long-term therapy (week 54); proportion of subjects with 50% or more reduction in AIMS score from study entry to end of long-term therapy (week 54); the proportion of subjects that achieved treatment effect at the end of long-term therapy (week 54) based on the patient's global impression of progress (PGIC) (in which treatment effect is defined as strong improvement or very strong improvement); percentage change in AIMS score from start of this study to end of long-term therapy (week 54); and based on the change in AIMS score from the start of this study to the end of long-term therapy (week 54), as assessed by blinded centralized video assessment, the cumulative proportion of responders ranged from 10% improvement from study start to 90% improvement from study start in increments of 10 - percentage points.

results

The results are shown in FIG. 9, which demonstrates that by week 6 of the study, more than 50% of the subjects had a strong improvement or a very strong improvement according to PGIC and CGIC.

ARM-TD

An additional clinical trial, the Movement Reduction in Tardive Dyskinesia (ARM-TD), was designed and conducted to evaluate the efficacy of SD-809 (deutetrabenazine) in the treatment of moderate to severe tardive dyskinesia. The ARM-TD study was a 1:1 randomized, double-blind, placebo-controlled, parallel cohort study of 117 patients in total (of which 104 patients completed the trial) with moderate to severe tardive dyskinesia.

The objects were selected for inclusion in the study as follows. Inclusion criteria included age 18 to 75 inclusive; history of use of a dopamine receptor antagonist for at least 3 months (or 1 month in subjects 60 years of age and older); clinical diagnosis of TD and symptoms for at least 3 months prior to screening; TD symptoms disturb the subject or cause functional impairment; subject has moderate to severe pathological movements at the time of the visit at the start of the study, which, in the opinion of the investigator, is based on AIMS item 8 and the AIMS total reference value (>6) (according to

- 30 042209 in accordance with paragraphs 1-7) according to the assessment of the responsible researcher; for subjects with pre-existing mental illness, the subject is mentally stable and has no change in psychoactive medications (including, but not limited to, antipsychotics, benzodiazepines, anticonvulsants, and mood stabilizers) for >30 days prior to screening (45 days for antidepressants); subjects on long-acting drugs (depot) have been on stable therapy (dose, frequency) for >3 months prior to screening and the subject has a psychiatrist who is aware of the subject's participation in the trial and does not foresee any changes in the subject's treatment regimen (drug , dose, frequency) within the next 3 months; history of compliance with prescribed medications; the ability to swallow the study drug whole; written, informed consent; the subject is in good general health, lives in a stable environment, is expected to complete all study evaluations, and be properly supervised when necessary to comply with all study procedures, participate in all study visits, and participate safely in the study; sufficient reading skills to comprehend the rating scales filled in by objects; and, if the woman is of childbearing potential, she agrees to use acceptable methods of contraception from the time of screening until completion of the study if she is sexually active.

Exclusion criteria included: score >11 on the Hospital Anxiety and Depression Scale (HADS) subscale at screening or at study entry; developmentally delayed or showing signs of dementia; unstable or serious medical conditions at the time of screening or study entry; history (within 3 months) or presence of aggressive behavior; QTcF value >4 50 ms (men) or > 460 ms (women) or > 480 ms (with right bundle branch block [RBBB]) on 12-lead ECG at screening; evidence of liver failure at screening identified by: AST or ALT > 2.5 times the upper limit of normal (ULN) or ALP or total bilirubin > 2 times the ULN (where abnormalities in two or more of these ACT, ALT, ALP, TBil must be confirmed by a medical examination at study entry, but subjects with Gilbert's syndrome meet the eligibility criteria if approved by the Medical Examination), or prothrombin time > 4 s, or HBsAg positive; evidence of significant impairment of renal function at screening, as determined by creatinine clearance < 50 ml/min, as assessed by the Cockcroft-Gault formula; with a known allergy to tetrabenazine or to any of the components of deutetrabenazine; the subject has participated in a study investigating drugs or devices and received an investigational drug within 30 days (or 5 drug half-lives) of screening, whichever is greater; pregnant or breastfeeding at screening or at study entry; recognition of illicit drug use at screening; a history of alcohol or drug abuse in the previous 12 months, as defined by DSM-V, or the subject is unable to abstain from substance abuse during the study; and a positive drug screening urine test (for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, or opiates) at screening or at study entry, unless the subject is on a stable dose of a benzodiazepine.

Dosing

Enrolled patients received either deutetrabenazine or placebo, which was titrated from an initial dose of 6 mg deutetrabenazine (which, as in previous studies, provides an AUC of total (α+β)-HTBZ, which is comparable to 12.5 mg tetrabenazine) to optimal dosages from 12 to 48 mg/day for six weeks in increments of 6 mg/day per week. The drug was then administered at this dose for an additional six weeks for a total of 12 weeks of treatment followed by a 1 week washout period. Randomization for each group was 1:1 and was stratified by the use of dopamine receptor antagonists (current users vs. non-users). Deutetrabenazine or placebo tablets were supplied as 6, 9, 12, 15, and 18 mg tablets and were administered BID with meals in the morning and evening (recommended 10 hours apart, minimum 6 hours). Dose interruption was permitted for up to one week if the subject experienced a clinically significant adverse event.

Study Goals and Endpoints

The objectives of the study were to evaluate the efficacy of SD-809 in reducing the severity of pathological involuntary movements associated with tardive dyskinesia and the safety and tolerability of deutetrabenazine titration and maintenance therapy in subjects with drug-induced tardive dyskinesia. The primary efficacy endpoint is the change in AIMS score (items 1-7) from baseline to week 12, as assessed by blind centralized video assessment. The baseline AIMS score is defined for each subject as a day 0 score. The AIMS consists of 12 clinician-assigned and scorable items.

P.1-10 are evaluated on a 5-point scale with reference and consist of the following:

Items 1-4 evaluate orofacial movements;

Items 5-7 relate to lower extremity dyskinesia and truncal dyskinesia;

- 31 042209

Items 8-10 relate to the overall severity, as assessed by the investigator, and the patient's awareness of movements and associated impairments; And

Items 11-12 are yes/no questions regarding dental and/or denture problems, since such problems can be mistaken for dyskinesia.

The total score of claims 1-7 (orofacial movements, lower limb movements and truncal movements) can be calculated and represents the observed movements with higher scores indicating more severe dyskinesia. P.8 can be used as a general severity index; Items 9 and 10 provide additional information about patients' disability and awareness; and Items 11 and 12 provide information that may be useful in determining lip, jaw, and tongue movements.

The key secondary endpoints are: 1) the proportion of subjects that had an effect on treatment at week 12, based on the Clinical Global Impression of State Change (CGIC); 2) the proportion of subjects that had an effect on treatment at week 12, based on the overall impression of the patient's progress (PGIC); and 3) the change in the modified Cranial and Cervical Dystonia Questionnaire (CDQ-24) from baseline to week 12. How and in previous studies, the effect of PGIC/CGIC treatment can be defined as a strong or very strong improvement on a 7-point Likert scale, ranging from very strong deterioration to very strong improvement at week 12. CDQ-24 is a disease-specific questionnaire to determine quality of life , designed for patients with cranial and cervical dystonia, including both cervical dystonia (CD) and blepharospasm (BPS). CDQ-24 was chosen for use in the present study because it includes domains that are relevant not only to CD and BPS, but also to TD, such as stigma, emotional well-being, pain, daily activities, and social/family life. For the present study, CDQ-24 was modified so that the questions focus more specifically on the impact of TD (as opposed to CD/BPS) on quality of life.

Additional secondary endpoints included: 1) percentage change in AIMS score (central rating) from baseline to week 12; 2) based on change in AIMS score (central score) from baseline to week 12, cumulative response rates for response levels ranging from 10% improvement from baseline to 90% improvement from baseline in increments of 10 percentage points and 3 ) change in AIMS score (items 1-7) from baseline to week 12, as assessed by the local expert, where the baseline AIMS score is determined for each object as the day 0 score.

Finally, in each clinical setting, an investigator experienced in assessing movement disorders was responsible for confirming the diagnosis of TD, performing all clinical assessments, and making decisions about dose adjustments of study drug. Safety was also monitored by adverse event reporting and other measures including, but not limited to, UPDRS, BARS, HADS, C-SSRS, ESS, and MoCA.

Measurements and statistics

Digital video recordings of AIMS scores taken at all clinic visits (screening, baseline, Weeks 2, 4, 6, 9, and 12) were assessed by pairs of central assessors who are experts in movement disorders and blinded. by treatment group, video sequence, and by AIMS score by investigator. The analysis was performed using a linear mixed repeated measures model (MMRM) with change in the AIMS score as the dependent variable. The model included fixed effects for treatment group, time point (five levels: weeks 2, 4, 6, 9, and 12), treatment group for time interaction, and randomization variable for stratification. An unstructured covariance model was used and the primary analysis compared the deutetrabenazine and placebo groups at week 12 using a two-tailed test with a 5% significance level.

Efficiency Results

Top-level data showed that the study met its primary endpoint. Patients treated with deutetrabenazine achieved an improvement of 3 points on the AIMS scale from study entry to end of therapy compared with 1.6 points in the placebo group (p = 0.0188) for a clinically meaningful effect. In addition, secondary endpoints numerically favored deutetrabenazine. The results are shown in table. 22.

Table 22

DTBZ (N=56) Placebo (N=57) Difference in treatment AIMS change (LS mean) -3 -16 -1.4 (p-value 0.0188) PGIC N treatment effect (%) 42.90% 29.80% 13.00% Effect of CGIC treatment (%) 48.20% 40.40% 7.90% change from start of mCDQ-24 study* -11.1 -8.3 -2.7

- 32 042209

Security Results

The study also showed a favorable safety and tolerability profile for deutetrabenazine, including low levels of depression, drowsiness, insomnia, and akathisia. Fewer deutetrabenazine patients than placebo experienced serious adverse events (SAEs) (4 patients [6.9%] in the deutetrabenazine group versus 6 [10.2%] in the placebo group, none of the SAEs were treatment related ), or who experienced adverse events leading to discontinuation (1 patient [1.7%] versus 2 patients [3.4%]). Neuropsychiatric adverse events in this patient population were rarely associated with SD-809 treatment compared with placebo and included drowsiness/sedation (9 [15.5%] versus 6 [10.2%]), insomnia (4 [6.9 %] vs. 1 [1.7%]), akathisia (3 [5.2%] vs. 0 [0.0%]) (depression/depressed mood was reported by one patient in each treatment group, and suicidal ideation was reported by one placebo versus none in SD-809 Three patients discontinued treatment due to adverse events (1 in the deutetrabenazine group versus 2 in the placebo group) For all other adverse events reported in the study, scores in the deutetrabenazine group were the same or lower than in the placebo group.The results are presented below in Table 23, which includes adverse events observed in 3 or more subjects.

Table 23

DTBZ (n=58) Placebo (n=59) Any TEAE (adverse events occurring during treatment) 41 (70.7%) 36 (61.0%) Serious TEAE 41 (70.7%) 36 (61.0%) TEAE arising from withdrawal from the study 4 (6.9%) 6 (10.2%) Nervous System Disorders 1 (1.7%) 2 (3.4%) 6 (10.2%) 9 (15.5%) 6 (10.2%) 6 (10.2%) 4 (6.9%) 6 (10.2%) 3 (5.1%) 2 (3.4%) 3 (5.1%) 0 (0.0%) Psychiatric disorders 3 (5.2%) 0 (0.0%) 4 (6.8%) 3 (5.2%) 4 (6.8%) 1 (1.7%) Gastrointestinal Disorders 4 (6.9%) 1 (1.7%) 6 (10.2%) 2 (3.4%) 6 (10.2%) 3 (5.1%) 3 (5.2%) 3 (5.1%) 2 (3.4%) 2 (3.4%) 2 (3.4%) 2 (3.4%) 2 (3.4%) 2 (3.4%) 3 (5.1%) General disorders 1 (1.7%) 3 (5.1%) 5 (8.5%) 4 (6.9%) 5 (8.5%) 2 (3.4%) Infections and infestations 1 (1.7%) 2 (3.4%) 4 (6.8%) 2 (3.4%) 4 (6.8%) 1 (1.7%) 2 (3.4%) 1 (1.7%) 2 (3.4%)

Based on the studies disclosed herein, deutetrabenazine, other deuterium-substituted tetrabenazines, and valbanazine are expected to be effective in the treatment of tardive dyskinesia and other movement disorders and symptoms such as dyskinesias, typically dystonia, ballismus, akinesia, and parkinsonism, and that The dosing regimens and methods described herein will provide significant benefits to patients.

Conclusion

These results support the fact that the differentiated pharmacokinetic profile and lower Cmax associated with deutetrabenazine compared to tetrabenazine improves the safety profile of deutetrabenazine by reducing the risk of life-threatening arrhythmias. From the foregoing description, a person skilled in the art can determine the main characteristics of this invention and, without departing from its spirit and scope, can make various changes and modifications to the invention to adapt it to various applications and conditions.

Claims (40)

1. A method of transferring a person from tetrabenazine to deutetrabenazine for the treatment of chorea associated with Huntington's disease, wherein the method comprises: a) cancellation of the daily amount of tetrabenazine; b) the next day, administering to the person an initial daily amount of deutetrabenazine, wherein the daily amount of tetrabenazine is 12.5 mg and the initial total daily amount of deutetrabenazine is 6 mg; the daily amount of tetrabenazine is 25 mg, and the initial total daily amount of de- utetrabenazine is 12 mg; the daily amount of tetrabenazine is 37.5 mg, and the initial total daily amount of deutetrabenazine is 18 mg; the daily amount of tetrabenazine is 50 mg, and the initial total daily amount of deutetrabenazine is 24 mg; the daily amount of tetrabenazine is 62.5 mg, and the initial total daily amount of deutetrabenazine is 30 mg; the daily amount of tetrabenazine is 75 mg, and the initial total daily amount of deutetrabenazine is 36 mg; the daily amount of tetrabenazine is 87.5 mg and the initial total daily amount of deutetrabenazine is 42 mg or the daily amount of tetrabenazine is 100 mg and the initial total daily amount of deutetrabenazine is 48 mg. 2. The method according to claim 1, characterized in that as a result of the transition, the degree of control of chorea is improved, as indicated by a decrease of at least 0.5 points on the scale of assessment of the total maximum chorea (TMS). 3. The method of claim 2, wherein the improvement is measured from baseline to maintenance therapy. 4. The method according to claim 1, characterized in that the transition leads to a reduction in chorea by at least 15%. 5. The method according to claim 1, characterized in that: (i) the transition results in a reduction in chorea of at least 10% and said method also satisfies one or more of the following conditions: motor function improves by at least 10%; the physical functioning of the object is improved; swallowing improves; balance does not deteriorate; treatment does not cause a significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia and the maximum increase in QTcF is less than 5 ms; or: (ii) motor function is improved by at least 10% and said method also provides for one or more of the following: chorea is reduced by at least 10%; the physical functioning of the object is improved; swallowing improves; balance does not deteriorate; treatment does not cause a significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism, or dysphagia, and the maximum increase in QTcF is less than 5 ms. 6. The method according to claim 1, characterized in that the initial daily dose is 12, 18, 24, 30, 36, 42 or 48 mg and the initial daily dose is administered in two doses. 7. The method according to claim 6, characterized in that the first dose is 6 mg and the second dose is 6 mg; the first dose is 9 mg and the second dose is 9 mg; the first dose is 12 mg and the second dose is 12 mg; the first dose is 15 mg and the second dose is 15 mg; the first dose is 18 mg and the second dose is 18 mg; the first dose is 21 mg and the second dose is 21 mg or the first dose is 24 mg and the second dose is 24 mg. 8. The method of claim 7, further comprising: c) after about one week, determine the degree of control of abnormal involuntary movements achieved with the initial daily dose of deutetrabenazine, and the tolerability of the initial daily dose of deutetrabenazine; And d) increasing the daily dose of deutetrabenazine by 6 mg/day to a subsequent daily dose of deutetrabenazine if switching does not result in at least maintenance of chorea control and the initial daily dose is tolerable. 9. The method of claim 8, further comprising: e) after about one week, repeat steps c) and d) in those people in whom abnormal involuntary movements are reduced and the daily amount of deutetrabenazine is well tolerated. 10. The method according to claim 9, which consists in reducing the amount of deutetrabenazine by 6 mg / day to - 34 042209 the next daily amount in those people in whom any subsequent daily amount is intolerable. 11. The method of claim 9, further comprising repeating step e) until the degree of control of abnormal involuntary movements is adequate and the daily amount of deutetrabenazine is tolerable. 12. The method according to claim 1, characterized in that the initial daily dose is 6 mg and is administered in a single dose. 13. The method according to claim 1, characterized in that the initial daily amount of deutetrabenazine is 6, 12, 18, 24, 30, 36 or 42 mg, further comprising: c) after about one week, determine the degree of control of abnormal involuntary movements achieved with the initial daily dose of deutetrabenazine, and the tolerability of the initial daily dose of deutetrabenazine; And d) increasing the daily dose of deutetrabenazine by 6 mg/day to a subsequent daily dose in those people in whom switching does not result in at least maintenance of chorea control and the initial daily amount is tolerable. 14. The method according to claim 13, characterized in that the subsequent daily amount is 12, 18, 24, 30, 36 or 42 mg, further comprising: e) after about one week, repeat steps c) and d) in those patients in whom abnormal involuntary movements have decreased and the daily dose of deutetrabenazine is tolerable. 15. The method according to claim 14, characterized in that the daily dose is 18, 24, 30, 36, or 42 mg, further comprising repeating step e) until the degree of control over abnormal involuntary movements becomes adequate, and the daily dose deutetrabenazine tolerated. 16. The method of claim 15 wherein the total maximum daily dose is 48 mg. 17. The method of claim 15 wherein the total maximum daily dose is 36 mg. 18. The method of claim 17 wherein the individual is simultaneously receiving a strong inhibitor of CYP2D6. 19. The method of claim 18, wherein the strong CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or ritonavir. 20. The method of claim 19 wherein the potent inhibitor of CYP2D6 is paroxetine, fluoxetine, or bupropion. 21. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 12.5 mg, and the initial total daily amount of deutetrabenazine is 6 mg. 22. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 25 mg, and the initial total daily amount of deutetrabenazine is 12 mg. 23. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 6 mg and the second dose being 6 mg. 24. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 37.5 mg, and the initial total daily amount is increased by 6 mg/day to a subsequent daily amount of deutetrabenazine equal to 18 mg. 25. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 9 mg and the second dose being 9 mg. 26. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 50 mg, and the initial total daily amount of deutetrabenazine is 24 mg. 27. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 12 mg and the second dose being 12 mg. 28. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 62.5 mg, and the initial total daily amount of deutetrabenazine is 30 mg. 29. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 15 mg and the second dose being 15 mg. 30. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 75 mg, and the initial total daily amount of deutetrabenazine is 36 mg. 31. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 18 mg and the second dose being 18 mg. 32. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 87.5 mg, and the initial total daily amount of deutetrabenazine is 42 mg. 33. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 21 mg and the second dose being 21 mg. 34. The method according to claim 1, characterized in that the daily amount of tetrabenazine is 100 mg, and the initial total daily amount of deutetrabenazine is 48 mg. 35. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, the first dose being 24 mg and the second dose being 24 mg. 36. The method of claim 1, wherein the transition results in at least maintaining control of chorea in the individual. - 35 042209 37. The method according to claim 1, characterized in that the initial total daily amount of deutetrabenazine is 6, 12, 18, 24, 30 or 36 mg. 38. The method of claim 37, wherein the individual is simultaneously receiving a strong inhibitor of CYP2D6. 39. The method of claim 38, wherein the strong CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or ritonavir. 40. The method of claim 38 wherein the strong CYP2D6 inhibitor is paroxetine, fluoxetine, or bupropion. i ₆ . 5-1-------1----------------1----------------1----- ------------1-------------------------1------------ -------------1--------1----------------1------0 2 4 6 9 12 13 End point ^{P0DD study week} ? SD-809, m: 45 45 44 44 45 45 4445 Placebo, n: 45 45 45 44 42 43 4345 Fig. 1 SD ^- 809 .... ^Placebo SD-809, GT 45 44 44 45 45 44 Placebo, n: 45 45 44 42 43 42 -1 O 1 23456789 10 11 12 13 14 15 Research Week Fig. 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Research Week Fig. 3 - 36 042209 Research Week Fig. 4A Fig. 4V Fig. 4C Total Maximal Chorea Scale Score (mean change from baseline) 37 patients: on a stable dose of ^: tetrabenazine ^; Night switch on SD-809 42.1MG 203 MY 29./MY ................................33.9 MY; T8Z SD-8G9 SD-8D9 5D-809 η = 37 π = 3δ n = 21 ; Initial level 1 (ΤΒΖ) 2 3 4 5 6 7 8* (Weeks on SD-809 therapy) Fig. 5 - 37 042209 Gross Motor Function Scale Score (Mean change from baseline) 37 patients ^; at a stable dose; tetrabenazine; = Night switch to SD-809 sD-m -S0W 01-809 η = 24 T3Z _: Baseline (TBZ) 8** (Weeks on SD-809 therapy) D-0 0218 'P-0Ό279 Fig. 6 Swallowing Problem Questionnaire Score Night switch on SD-809 sow SD-8C9 bD-309 n = 15 SD-8119 (Weeks on SD-809 Therapy) Fig. 7 Fig. 8 Fig. 9 - 38 042209 Decrease in TS-CGI from start of study to week 8 . Decreased TS-CGI score < I Fig. 10 PGIC at week 8 Week 8 PGIC score _Ε====== ^ Fig. AND