U.S. patent application number 15/428868 was filed with the patent office on 2017-06-01 for methods for the treatment of abnormal involuntary movement disorders.
The applicant listed for this patent is Auspex Pharmaceuticals, Inc.. Invention is credited to Michael Fangching Huang, David Stamler.
Application Number | 20170151227 15/428868 |
Document ID | / |
Family ID | 55590145 |
Filed Date | 2017-06-01 |
United States Patent
Application |
20170151227 |
Kind Code |
A1 |
Stamler; David ; et
al. |
June 1, 2017 |
METHODS FOR THE TREATMENT OF ABNORMAL INVOLUNTARY MOVEMENT
DISORDERS
Abstract
Disclosed herein are new dosage regimens for
deuterium-substituted benzoquinoline compounds, and methods for the
treatment of abnormal muscular activity, movement disorders, and
related conditions.
Inventors: |
Stamler; David; (Menlo Park,
CA) ; Huang; Michael Fangching; (Ladera Ranch,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Auspex Pharmaceuticals, Inc. |
La Jolla |
CA |
US |
|
|
Family ID: |
55590145 |
Appl. No.: |
15/428868 |
Filed: |
February 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15063068 |
Mar 7, 2016 |
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15428868 |
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62129616 |
Mar 6, 2015 |
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62175112 |
Jun 12, 2015 |
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62180012 |
Jun 15, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4745 20130101;
A61P 25/16 20180101; A61P 1/08 20180101; A61P 25/24 20180101; A61K
9/20 20130101; A61K 31/4375 20130101; A61P 1/04 20180101; A61K
31/473 20130101; A61P 3/02 20180101; A61K 9/2027 20130101; A61P
25/22 20180101; A61P 25/14 20180101; A61K 9/2013 20130101; A61K
45/06 20130101; A61P 3/04 20180101; A61P 25/20 20180101; A61K
9/2054 20130101; A61K 9/2018 20130101 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of treating abnormal involuntary movement in a subject
with impaired CYP2D6 metabolism, comprising: administering to the
subject a total daily dose of deutetrabenazine of less than or
equal to about 48 mg.
2. The method of claim 1, wherein the total daily dose of
deutetrabenazine is less than 48 mg.
3. The method of claim 1, wherein the total daily dose of
deutetrabenazine is less than or equal to about 36 mg.
4. The method of claim 1, wherein the total daily dose of
deutetrabenazine is less than about 36 mg.
5. The method of claim 1, wherein the subject is concurrently
receiving a strong CYP2D6 inhibitor.
6. The method of claim 5, wherein the strong CYP2D6 inhibitor is
fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or
ritonavir.
7. The method of claim 5, wherein the strong CYP2D6 inhibitor is
paroxetine, fluoxetine, or bupropion.
8. The method of claim 1, wherein the subject's impaired CYP2D6
metabolism is genetic.
9. The method of claim 1, resulting in no clinically significant
adverse event in the subject.
10. The method of claim 1, resulting in no significant increase in
insomnia, depression, anxiety, agitation, suicidal ideation,
akathisia, irritability, fatigue, parkinsonism or dysphagia in the
subject.
11. The method of claim 1, wherein the abnormal involuntary
movement is caused by a movement disorder.
12. The method of claim 11, wherein the movement disorder is
akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia,
cerebral palsy, chorea, corticobasal degeneration, dyskinesias
(e.g., paroxysmal), dystonia (general, segmental, or focal)
including blepharospasm, writer's cramp (limb dystonia), laryngeal
dystonia (spasmodic dysphonia), and oromandibular dystonia,
essential tremor, geniospasm, hereditary spastic paraplegia,
Huntington's Disease, multiple system atrophy (Shy Drager
Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease
levodopa-induced dyskinesia, parkinsonism, progressive supranuclear
palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis
(cervical dystonia), spasticity due to stroke, cerebral palsy,
multiple sclerosis, spinal cord or brain injury, stereotypic
movement disorder, stereotypy, Sydenham's Chorea, synkinesis,
tardive dyskinesia, dystonia, tics, Tourette syndrome, or Wilson's
Disease.
13. The method of claim 11, wherein the movement disorder is a
hyperkinetic movement disorder.
14. The method of claim 11, wherein the movement disorder is
Huntington's disease, tardive dyskinesia, Tourette syndrome,
dystonia, or Parkinson's disease levodopa-induced dyskinesia.
15. The method of claim 11, wherein the movement disorder is
Huntington's disease, tardive dyskinesia, or Tourette syndrome.
16. The method of claim 11, wherein the movement disorder is
Huntington's disease.
17. The method of claim 1, wherein the abnormal involuntary
movement is chorea, akathisia, dyskinesia, tremor, or tic.
18. The method of claim 1, wherein the total daily dose of
deutetrabenazine is administered in two doses.
19. The method of claim 1, resulting in an improvement in balance,
physical functioning, or swallowing in the subject.
20. The method of claim 19, wherein the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale after baseline.
21. The method of claim 1, resulting in an improvement in motor
function in the subject.
22. The method of claim 21, wherein the motor function in the
subject is improved by a reduction of at least 1 point as measured
by the Total Motor Score (TMS) of the Unified Huntington's Disease
Rating Scale (UHDRS).
23. The method of claim 22, wherein the reduction in TMS Score is
at least 2, 3, or 4 points.
24. The method of claim 1, further comprising administering to the
subject another therapeutic agent useful in the treatment of
VMAT2-mediated disorders.
25. The method of claim 1, wherein the subject is human.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 15/063,068, filed Mar. 7, 2016, which claims the benefit of
priority of U.S. Provisional Applications No. 62/129,616, filed
Mar. 6, 2015, No. 62/175,112, filed Jun. 12, 2015, and No.
62/180,012, filed Jun. 15, 2015, the entireties of which are
incorporated herein by reference.
[0002] Disclosed herein are new dosing regimens for
deuterium-substituted benzoquinoline compounds, and methods for the
treatment of abnormal involuntary movements, abnormal muscular
activity, movement disorders, and related conditions.
[0003] Movement disorders are neurological conditions that affect
the speed, fluency, quality, and ease of movement. Movement
disorders can be classified into two basic categories: those
characterized by disordered or excessive movement (referred to as
"dyskinesia" and "hyperkinesia" or "hyperkinetic movement
disorders," respectively), and those that are characterized by
slowness, or a lack of movement (referred to as "hypokinesia,"
"bradykinesia," or "akinesia"). An example of a "hyperkinetic"
movement disorder is chorea, such as that associated with
Huntington's disease (HD), while Parkinson's disease (PD) can be
classified as "hypokinetic," because it is often characterized by
slow, deliberate movements, or even freezing in place. Both
hyperkinetic and hypokinetic movement disorders can severely affect
a subject's quality of life, making daily tasks difficult.
Additionally, movement disorders can cause a subject physical pain
and increase the probability of accidents.
[0004] For example, chorea is an abnormal, involuntary, sudden
movement that can affect all muscle groups and flow randomly from
one body region to another; like many abnormal involuntary
movements, it is often alternatively referred to as a movement
disorder. Chorea is a hallmark of Huntington's Disease. In the
United States, an estimated 30,000 people have Huntington's
disease. As many as 90% of patients with HD experience chorea and
it is moderate to severe in approximately 70% of these patients. It
is considered by clinicians to be a serious condition, given its
significant interference with daily functioning and increased risk
for injury to the patient. In its early stages, chorea can
contribute to impaired speaking, writing, and activities of daily
living such as feeding, dressing, and bathing. In its later stages,
chorea can cause gait instability and poor postural control, with
an increased risk of serious injury from falling or from flailing
into objects. Severity of chorea and parkinsonism has been shown to
be independently associated with falls in later-stage patients with
HD. Dysphagia is a component of HD and can lead to recurrent
aspiration pneumonia, weight loss, and behavioral problems.
[0005] The American Academy of Neurology's guideline indicates
that, "Huntington's disease remains a devastating neurodegenerative
disease in need of neuroprotective and symptomatic treatments" and
that "treating chorea is an important part of Huntington's disease
management." A survey of 52 international experts indicated they
would treat chorea for the following reasons: 88% physical injury,
81% loss of balance, 77% social isolation, and 77% interference
with work. Despite this guidance, patients with HD who have chorea
are not often treated.
[0006] The only FDA-approved therapy in the United States for the
treatment of chorea associated with HD is tetrabenazine
(XENAZINE.RTM.), an inhibitor of VMAT2. Tetrabenazine reduces
presynaptic concentrations of monoamines, such as dopamine, in
neurons that regulate body movements. Although approximately 30,000
people in the United States are affected by HD and approximately
200,000 individuals may carry the gene and be at risk of developing
HD, according to a November 2013 presentation by Lundbeck, only
approximately 4,000 patients received this therapy. A substantial
majority of patients with chorea of HD are not receiving treatment
with tetrabenazine. Furthermore, based on interviews with
physicians in 2011, it is estimated that use of tetrabenazine in
hyperkinetic movement disorders other than the chorea of HD may
account for up to half of its use, indicating that as few as 2,000
patients with HD are receiving tetrabenazine. Additionally, a
report from the Baylor College of Medicine indicated that only 78
of the 349 hyperkinetic movement disorder patients treated with
tetrabenazine between 2006 and 2009 were patients with chorea.
Clearly, a substantial need for effective treatments for movement
disorders exists, and is only partially met by available
therapies.
[0007] In addition to chorea, impairment in overall motor symptoms
severely disrupt day-to-day functioning. The National Institutes of
Neurological Disorders and Stroke considers the Unified
Huntington's Disease Rating Scale (UHDRS) motor function
assessments in the Total Motor Score (TMS) to be a core outcome in
the evaluation of HD. All currently recruiting large Phase 2b/3
randomized clinical trials in patients with HD in the United States
are using UHDRS-TMS as their primary endpoint. Significant
correlations between the UHDRS-TMS and functional measures for
sleep, rest, eating, work, recreation and past-times, ambulation,
mobility, body care and movement, social interaction,
communication, physical, and psychosocial dimensions have been
shown in patients with HD. Higher UHDRS-TMS scores are associated
with a statistically significant lower likelihood of performing
work, managing finances, driving safely, supervising children, and
volunteering. Every 1-point worsening in the TMS was associated a
5% to 10% reduction in the likelihood of being able to complete
these certain tasks. The UHDRS-TMS is an independent predictor of
functional disability based on scales including the 36-Item
Short-Form Health Survey (SF-36).
[0008] Also in the United States, an estimated 500,000 patients
have the movement disorder tardive dyskinesia and experience
abnormal muscular activity. Tardive dyskinesia is a hyperkinetic
movement disorder that typically manifests as rapid, repetitive,
stereotypic movements that can be induced by certain drugs, such as
neuroleptics, such as dopamine receptor blocking agents, which are
used for treating psychiatric conditions, as well as by drugs such
as metoclopramide, which are used for treating various
gastrointestinal disorders. These patients are managed largely by
psychiatrists and movement disorder neurologists, and there are no
FDA-approved treatments for tardive dyskinesia.
[0009] Also in the United States, an estimated 100,000 children
have tics (abnormal involuntary movements or vocalizations)
associated with Tourette syndrome, with an estimated 27%
categorized as moderate to severe. Peak severity of the disorder is
around 12 years of age, with an estimated 13% to 22% of affected
children continuing to take medications for tics as adults. Few new
drugs have been introduced for treating a tic associated with
Tourette syndrome in more than 30 years; inadequacies can be
identified in the two approved neuroleptics and one
recently-approved dopamine antagonist. For example, these
treatments carry, among other adverse events, the risk of causing
permanent neurologic deficits, such as tardive dyskinesia.
[0010] Accordingly, there remains a need for improved compositions,
dosing regimens, and methods for the treatment of abnormal muscular
activity, abnormal involuntary movement and other related
disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows change in mean chorea score observed in
patients taking either deutetrabenazine or placebo from the
First-HD study.
[0012] FIG. 2 presents the mean change from baseline in swallowing
disturbance over time for deutetrabenazine and placebo (as
determined by questionnaire), demonstrating a significant
improvement in swallowing with deutetrabenazine treatment.
[0013] FIG. 3 presents the mean change from baseline in body weight
(kg) over time for deutetrabenazine and placebo from the First-HD
study.
[0014] FIG. 4 shows the mean total behavior score (A), anxiety (B)
and compulsive behavior (C) for deutetrabenazine-treated subjects
compared with the placebo group, from the First-HD study.
[0015] FIG. 5 shows change in mean chorea score observed in
patients switched from tetrabenazine to deutetrabenazine, and the
mean daily dose of tetrabenazine or deutetrabenazine corresponding
to the chorea score, from the ARC-HD study. In the figure, the
asterisk (*) at week 8 indicates p=0.0252.
[0016] FIG. 6 shows change in mean total motor score observed in
patients switched from tetrabenazine to deutetrabenazine from the
ARC-HD study.
[0017] FIG. 7 presents the mean change from baseline in swallowing
disturbance over time in patients switched from tetrabenazine to
deutetrabenazine (as determined by questionnaire) from the ARC-HD
study, demonstrating a trend toward improvement in swallowing with
deutetrabenazine treatment.
[0018] FIG. 8 shows the open-label long-term data in tardive
dyskinesia patients from a tardive dyskinesia study as percent of
treated subjects who were much improved or very much improved on a
seven-point Likert scale of Patient Global Impression of Change
(PGIC) and Clinical Global Impression of Change (CGIC).
[0019] FIG. 9 shows the mean change in motor, vocal, and combined
total tic scores in subjects treated in the pilot Tourette Syndrome
study, from baseline through the end of treatment at week 8 and
washout at week 9. The top line (triangles) represents the vocal
tic score; the middle line represents motor (squares) tic score,
and the bottom line (diamonds) represents the total (combined motor
and vocal) tic score. Treatment with deutetrabenazine lowered
(improved) both motor and vocal tics.
[0020] FIG. 10 shows the change in the Tourette Syndrome Clinical
Global Impression in subjects treated in the pilot Tourette
Syndrome study, from baseline through week 8; improvement is
measured by reduction in TS-CGI score.
[0021] FIG. 11 shows the Tourette Syndrome Patient Global
Impression of Change in subjects treated in the pilot Tourette
Syndrome study, at week 8; improvement is measured by positive
increase in TS-PGIC score wherein, e.g., 1 indicates minimally
improved; 2, much improved; and 3, very much improved.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Disclosed herein is a method of treating abnormal
involuntary movement in a subject, comprising: [0023] a)
administering to the subject an initial daily amount of a deuterium
substituted tetrabenazine comprising at least about 6 mg per day;
[0024] b) determining after about one week the degree of control of
abnormal involuntary movement achieved with the initial daily
amount and the tolerability of the initial daily amount; [0025] c)
increasing the daily amount of the deuterium substituted
tetrabenazine upward by 6 or more mg/day to a subsequent daily
amount if the degree of control of abnormal involuntary movement is
inadequate and the initial daily amount is tolerable; [0026] d)
optionally, repeating steps b) and c) until the degree of control
of abnormal involuntary movement is adequate and the daily amount
of the deuterium substituted tetrabenazine is tolerable; and [0027]
e) if any subsequent amount is intolerable, decreasing the daily
amount downward by 6 or more mg/day to a subsequent daily
amount.
[0028] Also disclosed is a method of treating abnormal involuntary
movement in a subject, comprising: [0029] a) administering to the
subject an initial daily amount of deutetrabenazine of at least
about 6 mg per day; [0030] b) determining after about one week the
degree of control of abnormal involuntary movement achieved with
the initial daily amount and the tolerability of the initial daily
amount; [0031] c) increasing the daily amount of the
deutetrabenazine upward by 6 mg/day to a subsequent daily amount if
the abnormal involuntary movement is not reduced and the initial
daily amount is tolerable; [0032] d) after about one week,
optionally, repeating steps b) and c) provided that abnormal
involuntary movement is reduced and the daily amount of the
deutetrabenazine is tolerable; and [0033] e) if any subsequent
amount is not tolerated, decreasing the daily amount downward by at
least 6 mg/day to a subsequent daily amount.
[0034] In certain embodiments, the abnormal involuntary movement is
caused by a movement disorder.
[0035] In certain embodiments, the movement disorder is chosen from
akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia,
cerebral palsy, chorea, corticobasal degeneration, dyskinesias
(e.g., paroxysmal), dystonia (general, segmental, or focal)
including blepharospasm, writer's cramp (limb dystonia), laryngeal
dystonia (spasmodic dysphonia), and oromandibular dystonia,
essential tremor, geniospasm, hereditary spastic paraplegia,
Huntington's Disease, multiple system atrophy (Shy Drager
Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease
levodopa-induced dyskinesia, parkinsonism, progressive supranuclear
palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis
(cervical dystonia), spasticity due to stroke, cerebral palsy,
multiple sclerosis, spinal cord or brain injury, stereotypic
movement disorder, stereotypy, Sydenham's Chorea, synkinesis,
tardive dyskinesia, tics, Tourette syndrome, and Wilson's
Disease.
[0036] In certain embodiments, the movement disorder is a
hyperkinetic movement disorder.
[0037] In certain embodiments, the abnormal involuntary movement is
chosen from chorea, akathisia, dyskinesia, tremor, and tic.
[0038] In certain embodiments, the abnormal involuntary movement is
chorea. In certain embodiments, the abnormal involuntary movement
is chorea associated with Huntington's disease. In certain
embodiments, the abnormal involuntary movement is a tic. In certain
embodiments, the abnormal involuntary movement is a tic associated
with Tourette syndrome.
[0039] In certain embodiments, movement disorder is chosen from
Huntington's disease, tardive dyskinesia, tics associated with
Tourette syndrome, dystonia, and Parkinson's disease
levodopa-induced dyskinesia.
[0040] In certain embodiments, the movement disorder is chosen from
Huntington's disease, tardive dyskinesia, and Tourette
syndrome.
[0041] In certain embodiments, the movement disorder is
Huntington's disease.
[0042] In certain embodiments, the movement disorder is chorea
associated with Huntington's disease.
[0043] In certain embodiments, the absence of a reduction or
suspension in an initial or subsequent daily amount indicates that
the daily amount is tolerable. In certain embodiments, the
tolerability is determined by assessment of one or more of the
subject's levels of depression, anxiety, insomnia, somnolence,
fatigue, dizziness, restlessness, agitation, irritability,
akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting
and nausea. In certain embodiments, a dose is not tolerated if one
or more of the foregoing occur. In certain embodiments, a dose is
not tolerated if somnolence or dizziness occur.
[0044] In certain embodiments, the deuterium substituted
tetrabenazine is deutetrabenazine. In certain embodiments, the
deutetrabenazine is a plus isomeric form of deutetrabenazine. In
certain embodiments, the plus isomeric form of deutetrabenazine is
an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a
plus isomeric form of tetrabenazine. In certain embodiments, the
plus isomeric form of tetrabenazine is an alpha isomer.
[0045] In certain embodiments, the initial daily amount of
deutetrabenazine is about 30% to about 70% of an existing total
daily amount of tetrabenazine that provides adequate control of the
abnormal involuntary movement. In certain embodiments, the initial
daily amount of deutetrabenazine is about 40% to about 60% of an
existing total daily amount of tetrabenazine that provides adequate
control of the abnormal involuntary movement. In certain
embodiments, the initial daily amount of deutetrabenazine is about
45% to about 55% of an existing total daily amount of tetrabenazine
that provides adequate control of the abnormal involuntary
movement. In certain embodiments, the initial daily amount of
deutetrabenazine is about 30% to about 50% of an existing total
daily amount of tetrabenazine that provides adequate control of the
abnormal involuntary movement.
[0046] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0047] In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48
mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about
78 mg. In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0048] In certain embodiments, the initial daily amount of
deutetrabenazine is administered in two doses, consisting of a
first dose and a second dose.
[0049] In certain embodiments:
[0050] the first dose about 6 mg and the second dose is about 6
mg;
[0051] the first dose about 9 mg and the second dose is about 9
mg;
[0052] the first dose about 12 mg and the second dose is about 12
mg;
[0053] the first dose about 15 mg and the second dose is about 15
mg;
[0054] the first dose about 18 mg and the second dose is about 18
mg;
[0055] the first dose about 21 mg and the second dose is about 21
mg;
[0056] the first dose about 24 mg and the second dose is about 24
mg;
[0057] the first dose about 27 mg and the second dose is about 27
mg;
[0058] the first dose about 30 mg and the second dose is about 30
mg;
[0059] the first dose about 33 mg and the second dose is about 33
mg;
[0060] the first dose about 36 mg and the second dose is about 36
mg; and
[0061] the first dose about 39 mg and the second dose is about 39
mg.
[0062] In certain embodiments:
[0063] the first dose about 6 mg and the second dose is about 6
mg;
[0064] the first dose about 9 mg and the second dose is about 9
mg;
[0065] the first dose about 12 mg and the second dose is about 12
mg;
[0066] the first dose about 15 mg and the second dose is about 15
mg;
[0067] the first dose about 18 mg and the second dose is about 18
mg;
[0068] the first dose about 21 mg and the second dose is about 21
mg; and
[0069] the first dose about 24 mg and the second dose is about 24
mg.
[0070] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0071] In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for a subject concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0072] In certain embodiments, the degree of chorea control is
improved by a reduction of at least 0.5 points on the Total Maximal
Chorea (TMC) score. In certain embodiments, the reduction in TMC
score is at least 1 point. In certain embodiments, the reduction in
TMC score is at least 1.5 points. In certain embodiments, the
reduction in TMC score is at least 2.0 points. In certain
embodiments, the reduction in TMC score is at least 2.5 points. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 8.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 10.0. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 12.0. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 12.7. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 14.0.
[0073] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0074] In certain embodiments, motor function is improved. In
certain embodiments, motor function is improved by a reduction of
at least 1 point on the Total Motor Score (TMS). In certain
embodiments, the reduction in TMS score is at least 2 points. In
certain embodiments, the reduction in TMS score is at least 3
points. In certain embodiments, the reduction in TMS score is at
least 4 points.
[0075] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is alleviated. In certain embodiments, treatment
reduces the symptoms of parkinsonism.
[0076] In certain embodiments, the treatment does not worsen
balance. In certain embodiments, the treatment improves
balance.
[0077] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0078] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0079] In certain embodiments, the treatment improves
swallowing.
[0080] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0081] In certain embodiments, treatment causes no significant
symptoms of parkinsonism or dysphagia.
[0082] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0083] Also provided are embodiments wherein any embodiment above
in paragraphs [023]-[054] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. As used herein, two embodiments are "mutually exclusive"
when one is defined to be something which cannot overlap with the
other. Also provided is the use of deutetrabenazine for treating
abnormal involuntary movement in a subject, as set forth herein or
in any of the embodiments above in paragraphs [023]-[054] above.
Also provided is the use of deutetrabenazine in the manufacture of
a medicament for treating abnormal involuntary movement in a
subject, as set forth herein or in any of the embodiments above in
paragraphs [023]-[054] above. Also provided is a composition
comprising deutetrabenazine for treating abnormal involuntary
movement in a subject, as set forth herein or in any of the
embodiments above in paragraphs [023]-[054] above.
[0084] Also provided is a method of transitioning a subject
receiving an existing total daily amount of tetrabenazine for
control of abnormal involuntary movement, comprising: [0085] a)
administering to the subject an initial daily amount of a deuterium
substituted tetrabenazine which is about 30% to about 70% of the
existing total daily amount of tetrabenazine and is at least about
6 mg per day; [0086] b) concurrently discontinuing the daily amount
of tetrabenazine; [0087] c) optionally, after about one week,
determining the degree of control of abnormal involuntary movement
achieved with the initial daily amount of a deuterium substituted
tetrabenazine and the tolerability of the initial amount; [0088] d)
optionally, if the degree of control of abnormal involuntary
movement is comparable to the control when the subject was
receiving tetrabenazine or inadequate and the initial amount is
tolerable, increasing the daily amount upward by 6 or more mg/day
to a subsequent daily amount; [0089] e) optionally, repeating steps
c) and d) until the degree of control of abnormal involuntary
movement is improved and the initial amount is tolerable; and
[0090] f) optionally, if any subsequent amount is intolerable,
decreasing the daily amount downward by 6 or more mg/day to a
subsequent daily amount.
[0091] Also provided is a method of transitioning a subject
receiving an existing daily amount of tetrabenazine for control of
abnormal involuntary movement from tetrabenazine to
deutetrabenazine, comprising: [0092] a) discontinuing the daily
amount of tetrabenazine; [0093] b) the next day, administering to
the subject an initial daily amount of deutetrabenazine, which is
about 30% to about 70% of the existing total daily amount of
tetrabenazine and is at least about 6 mg per day; [0094] c) after
about one week, determining the degree of control of abnormal
involuntary movement achieved with the initial daily amount of a
deuterium substituted tetrabenazine and the tolerability of the
initial amount; [0095] d) if the degree of control of abnormal
involuntary movement is comparable to the control when the subject
was receiving tetrabenazine or inadequate and the initial amount is
tolerated, increasing the daily amount upward by 6 mg/day to a
subsequent daily amount of deutetrabenazine; [0096] e) after about
one week, optionally, repeating steps c) and d) provided that
abnormal involuntary movement is reduced and the amount is
tolerated; and [0097] f) optionally, if any subsequent amount is
not tolerated, decreasing the daily amount downward by 6 mg/day to
a subsequent daily amount.
[0098] In certain embodiments, the initial daily amount of
deutetrabenazine is about 40% to about 60% of the existing total
daily amount of tetrabenazine and is at least about 6 mg per day.
In certain embodiments, the initial daily amount of
deutetrabenazine is about 45% to about 55% of the existing total
daily amount of tetrabenazine and is at least about 6 mg per day.
In certain embodiments, the initial daily amount of
deutetrabenazine is about 30% to about 50% of the existing total
daily amount of tetrabenazine and is at least about 6 mg per
day.
[0099] In certain embodiments, the abnormal involuntary movement is
caused by a movement disorder.
[0100] In certain embodiments, the movement disorder is chosen from
akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia,
cerebral palsy, chorea, corticobasal degeneration, dyskinesias
(e.g., paroxysmal), dystonia (general, segmental, or focal)
including blepharospasm, writer's cramp (limb dystonia), laryngeal
dystonia (spasmodic dysphonia), and oromandibular dystonia,
essential tremor, geniospasm, hereditary spastic paraplegia,
Huntington's Disease, multiple system atrophy (Shy Drager
Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease
levodopa-induced dyskinesia, parkinsonism, progressive supranuclear
palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis
(cervical dystonia), spasticity due to stroke, cerebral palsy,
multiple sclerosis, spinal cord or brain injury, stereotypic
movement disorder, stereotypy, Sydenham's Chorea, synkinesis,
tardive dyskinesia, tics, Tourette syndrome, and Wilson's
Disease.
[0101] In certain embodiments, the movement disorder is a
hyperkinetic movement disorder.
[0102] In certain embodiments, the abnormal involuntary movement is
chosen from chorea, akathisia, dyskinesia, tremor, and tic.
[0103] In certain embodiments, the abnormal involuntary movement is
chorea. In certain embodiments, the abnormal involuntary movement
is chorea associated with Huntington's disease. In certain
embodiments, the abnormal involuntary movement is a tic. In certain
embodiments, the abnormal involuntary movement is a tic associated
with Tourette syndrome.
[0104] In certain embodiments, movement disorder is chosen from
Huntington's disease, tardive dyskinesia, tics associated with
Tourette syndrome, dystonia, and Parkinson's disease
levodopa-induced dyskinesia.
[0105] In certain embodiments, the movement disorder is chosen from
Huntington's disease, tardive dyskinesia, and Tourette
syndrome.
[0106] In certain embodiments, the movement disorder is
Huntington's disease.
[0107] In certain embodiments, the movement disorder is chorea
associated with Huntington's disease.
[0108] In certain embodiments, the absence of a reduction or
suspension in an initial or subsequent daily amount indicates that
the daily amount is tolerable. In certain embodiments, the
tolerability is determined by assessment of one or more of the
subject's levels of depression, anxiety, insomnia, somnolence,
fatigue, dizziness, restlessness, agitation, irritability,
akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting
and nausea. In certain embodiments, a dose is not tolerated if one
or more of the foregoing occur. In certain embodiments, a dose is
not tolerated if somnolence or dizziness occur.
[0109] In certain embodiments, the deuterium substituted
tetrabenazine is deutetrabenazine. In certain embodiments, the
deutetrabenazine is a plus isomeric form of deutetrabenazine. In
certain embodiments, the plus isomeric form of deutetrabenazine is
an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a
plus isomeric form of tetrabenazine. In certain embodiments, the
plus isomeric form of tetrabenazine is an alpha isomer.
[0110] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0111] In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48
mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about
78 mg. In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg. In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0112] In certain embodiments, the initial daily amount of
deutetrabenazine is administered in two doses, consisting of a
first dose and a second dose.
[0113] In certain embodiments:
[0114] the first dose about 6 mg and the second dose is about 6
mg;
[0115] the first dose about 9 mg and the second dose is about 9
mg;
[0116] the first dose about 12 mg and the second dose is about 12
mg;
[0117] the first dose about 15 mg and the second dose is about 15
mg;
[0118] the first dose about 18 mg and the second dose is about 18
mg;
[0119] the first dose about 21 mg and the second dose is about 21
mg;
[0120] the first dose about 24 mg and the second dose is about 24
mg;
[0121] the first dose about 27 mg and the second dose is about 27
mg;
[0122] the first dose about 30 mg and the second dose is about 30
mg;
[0123] the first dose about 33 mg and the second dose is about 33
mg;
[0124] the first dose about 36 mg and the second dose is about 36
mg; and
[0125] the first dose about 39 mg and the second dose is about 39
mg.
[0126] In certain embodiments:
[0127] the first dose about 6 mg and the second dose is about 6
mg;
[0128] the first dose about 9 mg and the second dose is about 9
mg;
[0129] the first dose about 12 mg and the second dose is about 12
mg;
[0130] the first dose about 15 mg and the second dose is about 15
mg;
[0131] the first dose about 18 mg and the second dose is about 18
mg;
[0132] the first dose about 21 mg and the second dose is about 21
mg; and
[0133] the first dose about 24 mg and the second dose is about 24
mg.
[0134] In certain embodiments:
[0135] the existing total daily amount of tetrabenazine is about
12.5 mg and the initial daily amount of deutetrabenazine is about 6
mg;
[0136] the existing total daily amount of tetrabenazine is about 25
mg and the initial daily amount of deutetrabenazine is about 12
mg;
[0137] the existing total daily amount of tetrabenazine is about
37.5 mg and the initial daily amount of deutetrabenazine is about
18 mg;
[0138] the existing total daily amount of tetrabenazine is about 50
mg and the initial daily amount of deutetrabenazine is about 24
mg;
[0139] the existing total daily amount of tetrabenazine is about
62.5 mg and the initial daily amount of deutetrabenazine is about
30 mg;
[0140] the existing total daily amount of tetrabenazine is about 75
mg and the initial daily amount of deutetrabenazine is about 36
mg;
[0141] the existing total daily amount of tetrabenazine is about
87.5 mg and the initial daily amount of deutetrabenazine is about
42 mg; or
[0142] the existing total daily amount of tetrabenazine is about
100 mg and the initial daily amount of deutetrabenazine is about 48
mg.
[0143] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0144] In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for subjects concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0145] In certain embodiments, the chorea control is improved by a
reduction of at least 0.5 points on the Total Maximal Chorea (TMC)
score. In certain embodiments, the reduction in TMC score is at
least 1 point. In certain embodiments, the reduction in TMC score
is at least 1.5 points. In certain embodiments, the reduction in
TMC score is at least 2.0 points. In certain embodiments, the
reduction in TMC score is at least 2.5 points. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 8.0. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 10.0. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 12.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 12.7. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 14.0.
[0146] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0147] In certain embodiments, motor function is improved.
[0148] In certain embodiments, motor function is improved by a
reduction of at least 1 point on the Total Motor Score (TMS). In
certain embodiments, the reduction in TMS score is at least 2
points. In certain embodiments, the reduction in TMS score is at
least 3 points. In certain embodiments, the reduction in TMS score
is at least 4 points.
[0149] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is alleviated. In certain embodiments, treatment
reduces the symptoms of parkinsonism.
[0150] In certain embodiments, the treatment does not worsen the
subject's balance. In certain embodiments, the treatment improves
balance.
[0151] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0152] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0153] In certain embodiments, the treatment improves
swallowing.
[0154] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0155] In certain embodiments, treatment causes no significant
parkinsonism or dysphagia.
[0156] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0157] Also provided are embodiments wherein any embodiment above
in paragraphs [056]-[090] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine for
transitioning a subject receiving an existing total daily amount of
tetrabenazine for control of abnormal involuntary movement, as set
forth herein or in any of the embodiments above in paragraphs
[056]-[090] above. Also provided is the use of deutetrabenazine in
the manufacture of a medicament for transitioning a subject
receiving an existing total daily amount of tetrabenazine for
control of abnormal involuntary movement, as set forth herein or in
any of the embodiments above in paragraphs [056]-[090] above. Also
provided is a composition comprising deutetrabenazine for use in
transitioning a subject receiving an existing total daily amount of
tetrabenazine for control of abnormal involuntary movement, as set
forth herein or in any of the embodiments above in paragraphs
[056]-[090] above.
[0158] Also provided is a method of treating a movement disorder in
a subject comprising the administration of a daily amount of a
VMAT2 inhibitor, wherein either:
[0159] chorea is reduced by at least 10% and any one or more of the
following are true: [0160] motor function is improved by at least
10%; [0161] the subject's physical functioning is improved; [0162]
swallowing is improved; [0163] balance is not worsened; [0164]
treatment causes no significant increase in insomnia, depression,
anxiety, agitation, suicidal ideation, akathisia, irritability,
fatigue, parkinsonism or dysphagia; and [0165] the maximal
increases in QTcF is less than 5 ms;
[0166] or motor function is improved by at least 10%, and any one
or more of the following are true: [0167] chorea is reduced by at
least 10%; [0168] the subject's physical functioning is improved;
[0169] swallowing is improved; [0170] balance is not worsened;
[0171] treatment causes no significant increase in insomnia,
depression, anxiety, agitation, suicidal ideation, akathisia,
irritability, fatigue, parkinsonism or dysphagia; and [0172] the
maximal increases in QTcF is less than 5 ms.
[0173] In certain embodiments, the movement disorder is chosen from
akathisia, akinesia, ataxia, athetosis, ballismus, bradykinesia,
cerebral palsy, chorea, corticobasal degeneration, dyskinesias
(e.g., paroxysmal), dystonia (general, segmental, or focal)
including blepharospasm, writer's cramp (limb dystonia), laryngeal
dystonia (spasmodic dysphonia), and oromandibular dystonia,
essential tremor, geniospasm, hereditary spastic paraplegia,
Huntington's Disease, multiple system atrophy (Shy Drager
Syndrome), myoclonus, Parkinson's Disease, Parkinson's disease
levodopa-induced dyskinesia, parkinsonism, progressive supranuclear
palsy, restless legs syndrome, Rett Syndrome, spasmodic torticollis
(cervical dystonia), spasticity due to stroke, cerebral palsy,
multiple sclerosis, spinal cord or brain injury, stereotypic
movement disorder, stereotypy, Sydenham's Chorea, synkinesis,
tardive dyskinesia, tics, Tourette syndrome, and Wilson's
Disease.
[0174] In certain embodiments, the movement disorder is a
hyperkinetic movement disorder.
[0175] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is alleviated. In certain embodiments, treatment
reduces the symptoms of parkinsonism.
[0176] In certain embodiments, the movement disorder is chosen from
Huntington's disease, tardive dyskinesia, and tics associated with
Tourette syndrome.
[0177] In certain embodiments, the movement disorder is
Huntington's disease. In certain embodiments, the movement disorder
is chorea associated with Huntington's disease.
[0178] In certain embodiments, the movement disorder is a tic. In
certain embodiments, the movement disorder is a tic associated with
Tourette syndrome.
[0179] In certain embodiments, the VMAT2 inhibitor is a deuterium
substituted tetrabenazine. In certain embodiments, the deuterium
substituted tetrabenazine is deutetrabenazine. In certain
embodiments, the deutetrabenazine is a plus isomeric form of
deutetrabenazine. In certain embodiments, the plus isomeric form of
deutetrabenazine is an alpha isomer. In certain embodiments, the
VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In
certain embodiments, the plus isomeric form of tetrabenazine is an
alpha isomer. In certain embodiments, the VMAT2 inhibitor is
valbenazine.
[0180] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0181] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0182] In certain embodiments, the daily amount of deutetrabenazine
is administered in two doses, consisting of a first dose and a
second dose.
[0183] In certain embodiments:
[0184] the first dose about 6 mg and the second dose is about 6
mg;
[0185] the first dose about 9 mg and the second dose is about 9
mg;
[0186] the first dose about 12 mg and the second dose is about 12
mg;
[0187] the first dose about 15 mg and the second dose is about 15
mg;
[0188] the first dose about 18 mg and the second dose is about 18
mg;
[0189] the first dose about 21 mg and the second dose is about 21
mg;
[0190] the first dose about 24 mg and the second dose is about 24
mg;
[0191] the first dose about 27 mg and the second dose is about 27
mg;
[0192] the first dose about 30 mg and the second dose is about 30
mg;
[0193] the first dose about 33 mg and the second dose is about 33
mg;
[0194] the first dose about 36 mg and the second dose is about 36
mg; and
[0195] the first dose about 39 mg and the second dose is about 39
mg.
[0196] In certain embodiments:
[0197] the first dose about 6 mg and the second dose is about 6
mg;
[0198] the first dose about 9 mg and the second dose is about 9
mg;
[0199] the first dose about 12 mg and the second dose is about 12
mg;
[0200] the first dose about 15 mg and the second dose is about 15
mg;
[0201] the first dose about 18 mg and the second dose is about 18
mg;
[0202] the first dose about 21 mg and the second dose is about 21
mg; and
[0203] the first dose about 24 mg and the second dose is about 24
mg.
[0204] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0205] In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for subjects concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0206] In certain embodiments, the chorea control is improved by a
reduction of at least 0.5 points on the Total Maximal Chorea (TMC)
score. In certain embodiments, the reduction in TMC score is at
least 1 point. In certain embodiments, the reduction in TMC score
is at least 1.5 points. In certain embodiments, the reduction in
TMC score is at least 2.0 points. In certain embodiments, the
reduction in TMC score is at least 2.5 points. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 8.0. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 10.0. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 12.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 12.7. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 14.0.
[0207] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0208] In certain embodiments, motor function is improved.
[0209] In certain embodiments, motor function is improved by a
reduction of at least 1 point on the Total Motor Score (TMS). In
certain embodiments, the reduction in TMS score is at least 2
points. In certain embodiments, the reduction in TMS score is at
least 3 points. In certain embodiments, the reduction in TMS score
is at least 4 points.
[0210] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is improved. In certain embodiments, treatment reduces
the symptoms of parkinsonism.
[0211] In certain embodiments, the treatment does not worsen the
subject's balance. In certain embodiments, the treatment improves
balance.
[0212] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0213] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0214] In certain embodiments, the treatment improves
swallowing.
[0215] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0216] In certain embodiments, treatment causes no significant
parkinsonism or dysphagia.
[0217] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0218] Also provided are embodiments as recited in any of the
embodiments above in paragraphs [089]-[0115], wherein either:
[0219] chorea is reduced by at least 10% and any two or more of the
following are true: [0220] motor function is improved by at least
10%; [0221] the subject's physical functioning is improved; [0222]
swallowing is improved; [0223] balance is not worsened; [0224]
treatment causes no significant increase in insomnia, depression,
anxiety, agitation, suicidal ideation, akathisia, irritability,
fatigue, parkinsonism or dysphagia; and [0225] the maximal
increases in QTcF is less than 5 ms;
[0226] or motor function is improved by at least 10%, and any two
or more of the following are true: [0227] chorea is reduced by at
least 10%; [0228] the subject's physical functioning is improved;
[0229] swallowing is improved; [0230] balance is not worsened;
[0231] treatment causes no significant increase in insomnia,
depression, anxiety, agitation, suicidal ideation, akathisia,
irritability, fatigue, parkinsonism or dysphagia; and [0232] the
maximal increases in QTcF is less than 5 ms.
[0233] Also provided are embodiments as recited in any of the
embodiments above in paragraphs [089]-[0115], wherein either:
[0234] chorea is reduced by at least 10% and any three or more of
the following are true: [0235] motor function is improved by at
least 10%; [0236] the subject's physical functioning is improved;
[0237] swallowing is improved; [0238] balance is not worsened;
[0239] treatment causes no significant increase in insomnia,
depression, anxiety, agitation, suicidal ideation, akathisia,
irritability, fatigue, parkinsonism or dysphagia; and [0240] the
maximal increases in QTcF is less than 5 ms;
[0241] or motor function is improved by at least 10%, and any three
or more of the following are true: [0242] chorea is reduced by at
least 10%; [0243] the subject's physical functioning is improved;
[0244] swallowing is improved; [0245] balance is not worsened;
[0246] treatment causes no significant increase in insomnia,
depression, anxiety, agitation, suicidal ideation, akathisia,
irritability, fatigue, parkinsonism or dysphagia; and [0247] the
maximal increases in QTcF is less than 5 ms.
[0248] Also provided are embodiments wherein any embodiment above
in paragraphs [092]-[0120] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of a VMAT2 inhibitor for
treating a movement disorder in a subject, as set forth herein or
in any of the embodiments above in paragraphs [092]-[0120] above.
Also provided is the use of a VMAT2 inhibitor in the manufacture of
a medicament for treating a movement disorder in a subject, as set
forth herein or in any of the embodiments above in paragraphs
[092]-[0120] above. Also provided is a composition comprising a
VMAT2 inhibitor for use in treating a movement disorder in a
subject, as set forth herein or in any of the embodiments above in
paragraphs [092]-[0120] above.
[0249] Also provided is a method of treating abnormal involuntary
movement in a subject, comprising administering an initial daily
amount of a VMAT2 inhibitor to the subject, in a manner that:
[0250] a) adequately reduces the subject's abnormal involuntary
movement; and [0251] b) improves one or more of the subject's
symptoms of anxiety, swallowing, body weight, irritability, overall
behavior, and compulsive behavior.
[0252] In further embodiments, the method comprises the additional
steps of: [0253] c) determining after about one week the degree of
control of abnormal involuntary movement achieved with the initial
daily amount and the tolerability of the initial daily amount; and
[0254] d) increasing the daily amount of the deuterium substituted
tetrabenazine upward by 6 or more mg/day to a subsequent daily
amount if the degree of control of abnormal involuntary movement is
inadequate and the initial daily amount is tolerable; [0255] e)
optionally, repeating steps b) and c) until the degree of control
of abnormal involuntary movement is adequate and the daily amount
of the deuterium substituted tetrabenazine is tolerable; and [0256]
f) if any subsequent amount is intolerable, decreasing the daily
amount downward by 6 or more mg/day to a subsequent daily
amount.
[0257] Also provided is a method of treating abnormal involuntary
movement in a subject, comprising administering a daily amount of
deutetrabenazine to the subject, which: [0258] a) adequately
reduces the subject's abnormal involuntary movement; and [0259] b)
improves one or more of the subject's symptoms of depression,
insomnia, somnolence, fatigue, dizziness, restlessness, agitation,
akathisia, parkinsonism, nausea, anxiety, impaired swallowing, body
weight gain, irritability, and compulsive behavior.
[0260] In certain embodiments, the method comprises the additional
steps of: [0261] c) determining after about one week of treatment
the degree of control of abnormal involuntary movement achieved
with the daily amount of deutetrabenazine (the initial daily
amount) and the tolerability of the initial daily amount; and
[0262] d) increasing the daily amount of the deuterium substituted
tetrabenazine upward by at least 6 mg/day to a subsequent daily
amount if abnormal involuntary movement is not reduced and the
initial daily amount is tolerated; [0263] e) after one week,
optionally, repeating steps b) and c) provided that abnormal
involuntary movement is reduced and the daily amount of the
deuterium substituted tetrabenazine is tolerated; and [0264] f) if
any subsequent amount is not tolerated, decreasing the daily amount
downward by 6 mg/day to a subsequent daily amount.
[0265] In certain embodiments, the abnormal involuntary movement is
a caused by a movement disorder.
[0266] In certain embodiments, the movement disorder is chosen from
chorea associated with Huntington's disease, tardive dyskinesia, a
tic associated with Tourette syndrome, dystonia, and and
Parkinson's disease levodopa-induced dyskinesia.
[0267] In certain embodiments, the movement disorder is chosen from
chorea associated with Huntington's disease, tardive dyskinesia,
and tics associated with Tourette syndrome.
[0268] In certain embodiments, the movement disorder is chorea
associated with Huntington's disease.
[0269] In certain embodiments, the abnormal muscular activity is a
tic. In certain embodiments, the abnormal muscular activity is a
tic associated with Tourette syndrome.
[0270] In certain embodiments, the daily amount of deutetrabenazine
improves one or more of the subject's symptoms of anxiety,
swallowing, body weight, irritability, overall behavior, and
compulsive behavior. In certain embodiments, the movement disorder
is chorea associated with Huntington's disease, and the daily
amount of deutetrabenazine improves one or more of the subject's
symptoms of depression, insomnia, somnolence, fatigue, dizziness,
restlessness, agitation, akathisia, parkinsonism, nausea, anxiety,
impaired swallowing, body weight gain, irritability, and compulsive
behavior. In certain embodiments, the movement disorder is chosen
from tardive dyskinesia and Tourette syndrome, and the daily amount
of deutetrabenazine improves one or more of the subject's symptoms
of depression, insomnia, somnolence, fatigue, dizziness,
restlessness, agitation, akathisia, parkinsonism, nausea, anxiety,
impaired swallowing, irritability, and compulsive behavior.
[0271] In certain embodiments, the absence of a reduction or
suspension in an initial or subsequent daily amount indicates that
the daily amount is tolerable. In certain embodiments, the
tolerability is determined by assessment of one or more of the
subject's levels of depression, anxiety, insomnia, somnolence,
fatigue, dizziness, restlessness, agitation, irritability,
akathisia, tardive dyskinesia, swallowing, parkinsonism, vomiting
and nausea. In certain embodiments, a dose is not tolerated if one
or more of the foregoing occur. In certain embodiments, a dose is
not tolerated if somnolence or dizziness occur.
[0272] In certain embodiments, the VMAT2 inhibitor is a deuterium
substituted tetrabenazine. In certain embodiments, the deuterium
substituted tetrabenazine is deutetrabenazine. In certain
embodiments, the deutetrabenazine is a plus isomeric form of
deutetrabenazine. In certain embodiments, the plus isomeric form of
deutetrabenazine is an alpha isomer. In certain embodiments, the
VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In
certain embodiments, the plus isomeric form of tetrabenazine is an
alpha isomer. In certain embodiments, the VMAT2 inhibitor is
valbenazine.
[0273] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0274] In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, about 48
mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg, and about
78 mg. In certain embodiments, the initial daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0275] In certain embodiments, the initial daily amount of
deutetrabenazine is administered in two doses, consisting of a
first dose and a second dose.
[0276] In certain embodiments:
[0277] the first dose about 6 mg and the second dose is about 6
mg;
[0278] the first dose about 9 mg and the second dose is about 9
mg;
[0279] the first dose about 12 mg and the second dose is about 12
mg;
[0280] the first dose about 15 mg and the second dose is about 15
mg;
[0281] the first dose about 18 mg and the second dose is about 18
mg;
[0282] the first dose about 21 mg and the second dose is about 21
mg;
[0283] the first dose about 24 mg and the second dose is about 24
mg;
[0284] the first dose about 27 mg and the second dose is about 27
mg;
[0285] the first dose about 30 mg and the second dose is about 30
mg;
[0286] the first dose about 33 mg and the second dose is about 33
mg;
[0287] the first dose about 36 mg and the second dose is about 36
mg; and
[0288] the first dose about 39 mg and the second dose is about 39
mg.
[0289] In certain embodiments:
[0290] the first dose about 6 mg and the second dose is about 6
mg;
[0291] the first dose about 9 mg and the second dose is about 9
mg;
[0292] the first dose about 12 mg and the second dose is about 12
mg;
[0293] the first dose about 15 mg and the second dose is about 15
mg;
[0294] the first dose about 18 mg and the second dose is about 18
mg;
[0295] the first dose about 21 mg and the second dose is about 21
mg; and
[0296] the first dose about 24 mg and the second dose is about 24
mg.
[0297] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg.
[0298] In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for subjects concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0299] In certain embodiments, the chorea control is improved by a
reduction of at least 0.5 points on the Total Maximal Chorea (TMC)
score. In certain embodiments, the reduction in TMC score is at
least 1 point. In certain embodiments, the reduction in TMC score
is at least 1.5 points. In certain embodiments, the reduction in
TMC score is at least 2.0 points. In certain embodiments, the
reduction in TMC score is at least 2.5 points. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 8.0. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 10.0. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 12.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 12.7. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 14.0.
[0300] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0301] In certain embodiments, motor function is improved.
[0302] In certain embodiments, motor function is improved by a
reduction of at least 1 point on the Total Motor Score (TMS). In
certain embodiments, the reduction in TMS score is at least 2
points. In certain embodiments, the reduction in TMS score is at
least 3 points. In certain embodiments, the reduction in TMS score
is at least 4 points.
[0303] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is improved. In certain embodiments, treatment reduces
the symptoms of parkinsonism.
[0304] In certain embodiments, the treatment does not worsen the
subject's balance. In certain embodiments, the treatment improves
balance.
[0305] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0306] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0307] In certain embodiments, the treatment improves
swallowing.
[0308] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0309] In certain embodiments, treatment causes no significant
parkinsonism or dysphagia.
[0310] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0311] Also provided are embodiments wherein any embodiment above
in paragraphs [0122]-[0152] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of a VMAT2 inhibitor for
treating abnormal involuntary movement in a subject, as set forth
herein or in any of the embodiments above in paragraphs
[0122]-[0152] above. Also provided is the use of a VMAT2 inhibitor
in the manufacture of a medicament for treating abnormal
involuntary movement in a subject, as set forth herein or in any of
the embodiments above in paragraphs [0122]-[0152] above. Also
provided is a composition comprising a VMAT2 inhibitor for use in
treating abnormal involuntary movement in a subject, as set forth
herein or in any of the embodiments above in paragraphs
[0122]-[0152] above.
[0312] Also provided is a method of reducing chorea and improving
motor function in a subject with Huntington's disease, comprising
the administration of a daily amount of a VMAT2 inhibitor.
[0313] In certain embodiments, the VMAT2 inhibitor is a deuterium
substituted tetrabenazine. In certain embodiments, the deuterium
substituted tetrabenazine is deutetrabenazine. In certain
embodiments, the deutetrabenazine is a plus isomeric form of
deutetrabenazine. In certain embodiments, the plus isomeric form of
deutetrabenazine is an alpha isomer. In certain embodiments, the
VMAT2 inhibitor is a plus isomeric form of tetrabenazine. In
certain embodiments, the plus isomeric form of tetrabenazine is an
alpha isomer. In certain embodiments, the VMAT2 inhibitor is
valbenazine.
[0314] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0315] In certain embodiments, the daily amount of deutetrabenazine
is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg,
about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg,
about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain
embodiments, the daily amount of deutetrabenazine is chosen from
about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg,
about 36 mg, about 42 mg, and about 48 mg.
[0316] In certain embodiments, the daily amount of deutetrabenazine
is administered in two doses, consisting of a first dose and a
second dose.
[0317] In certain embodiments:
[0318] the first dose about 6 mg and the second dose is about 6
mg;
[0319] the first dose about 9 mg and the second dose is about 9
mg;
[0320] the first dose about 12 mg and the second dose is about 12
mg;
[0321] the first dose about 15 mg and the second dose is about 15
mg;
[0322] the first dose about 18 mg and the second dose is about 18
mg;
[0323] the first dose about 21 mg and the second dose is about 21
mg;
[0324] the first dose about 24 mg and the second dose is about 24
mg;
[0325] the first dose about 27 mg and the second dose is about 27
mg;
[0326] the first dose about 30 mg and the second dose is about 30
mg;
[0327] the first dose about 33 mg and the second dose is about 33
mg;
[0328] the first dose about 36 mg and the second dose is about 36
mg; and
[0329] the first dose about 39 mg and the second dose is about 39
mg.
[0330] In certain embodiments:
[0331] the first dose about 6 mg and the second dose is about 6
mg;
[0332] the first dose about 9 mg and the second dose is about 9
mg;
[0333] the first dose about 12 mg and the second dose is about 12
mg;
[0334] the first dose about 15 mg and the second dose is about 15
mg;
[0335] the first dose about 18 mg and the second dose is about 18
mg;
[0336] the first dose about 21 mg and the second dose is about 21
mg; and
[0337] the first dose about 24 mg and the second dose is about 24
mg.
[0338] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine administered is less than or equal to
about 48 mg, or less than or equal to about 36 mg for subjects
concurrently receiving a strong CYP2D6 inhibitor. In certain
embodiments, the strong CYP2D6 inhibitor is chosen from fluoxetine,
paroxetine, bupropion, quinidine, cinacalcet, and ritonavir. In
certain embodiments, the strong CYP2D6 inhibitor is chosen from
paroxetine, fluoxetine, and bupropion.
[0339] In certain embodiments, the chorea control is improved by a
reduction of at least 0.5 points on the Total Maximal Chorea (TMC)
score. In certain embodiments, the reduction in TMC score is at
least 1 point. In certain embodiments, the reduction in TMC score
is at least 1.5 points. In certain embodiments, the reduction in
TMC score is at least 2.0 points. In certain embodiments, the
reduction in TMC score is at least 2.5 points. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 8.0. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 10.0. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 12.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 12.7. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 14.0.
[0340] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0341] In certain embodiments, motor function is improved.
[0342] In certain embodiments, motor function is improved by a
reduction of at least 1 point on the Total Motor Score (TMS). In
certain embodiments, the reduction in TMS score is at least 2
points. In certain embodiments, the reduction in TMS score is at
least 3 points. In certain embodiments, the reduction in TMS score
is at least 4 points.
[0343] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is improved. In certain embodiments, treatment reduces
the symptoms of parkinsonism.
[0344] In certain embodiments, the treatment does not worsen the
subject's balance. In certain embodiments, the treatment improves
balance.
[0345] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0346] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0347] In certain embodiments, the treatment improves
swallowing.
[0348] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0349] In certain embodiments, treatment causes no significant
parkinsonism or dysphagia.
[0350] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0351] Also provided are embodiments wherein any embodiment above
in paragraphs [0154]-[0173] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of a VMAT2 inhibitor for chorea
and improving motor function in a subject with Huntington's
disease, as set forth herein or in any of the embodiments above in
paragraphs [0154]-[0173] above. Also provided is the use of a VMAT2
inhibitor in the manufacture of a medicament for chorea and
improving motor function in a subject with Huntington's disease, as
set forth herein or in any of the embodiments above in paragraphs
[0154]-[0173] above. Also provided is a composition comprising a
VMAT2 inhibitor for use in chorea and improving motor function in a
subject with Huntington's disease, as set forth herein or in any of
the embodiments above in paragraphs [0154]-[0173] above.
[0352] Also provided is a method of improving motor function in a
subject with Huntington's disease, tardive dyskinseia, or Tourette
syndrome, comprising the administration of about a daily amount of
a VMAT2 inhibitor. In certain embodiments, the VMAT2 inhibitor is a
deuterium substituted tetrabenazine.
[0353] In certain embodiments, the subject has Huntington's
disease. In certain embodiments, the subject has tardive
dyskinseia. In certain embodiments, the subject has Tourette
syndrome.
[0354] In certain embodiments, the deuterium substituted
tetrabenazine is deutetrabenazine. In certain embodiments, the
deutetrabenazine is a plus isomeric form of deutetrabenazine. In
certain embodiments, the plus isomeric form of deutetrabenazine is
an alpha isomer. In certain embodiments, the VMAT2 inhibitor is a
plus isomeric form of tetrabenazine. In certain embodiments, the
plus isomeric form of tetrabenazine is an alpha isomer.
[0355] In certain embodiments, the VMAT2 inhibitor is
valbenazine.
[0356] In certain embodiments, the daily amount of deutetrabenazine
is administered in one dose or two doses.
[0357] In certain embodiments, the daily amount of deutetrabenazine
is chosen from about 6 mg, about 12 mg, about 18 mg, about 24 mg,
about 30 mg, about 36 mg, about 42 mg, about 48 mg, about 54 mg,
about 60 mg, about 66 mg, about 72 mg, and about 78 mg. In certain
embodiments, the daily amount of deutetrabenazine is chosen from
about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg,
about 36 mg, about 42 mg, and about 48 mg.
[0358] In certain embodiments, the daily amount of deutetrabenazine
is administered in two doses, consisting of a first dose and a
second dose.
[0359] In certain embodiments:
[0360] the first dose about 6 mg and the second dose is about 6
mg;
[0361] the first dose about 9 mg and the second dose is about 9
mg;
[0362] the first dose about 12 mg and the second dose is about 12
mg;
[0363] the first dose about 15 mg and the second dose is about 15
mg;
[0364] the first dose about 18 mg and the second dose is about 18
mg;
[0365] the first dose about 21 mg and the second dose is about 21
mg;
[0366] the first dose about 24 mg and the second dose is about 24
mg;
[0367] the first dose about 27 mg and the second dose is about 27
mg;
[0368] the first dose about 30 mg and the second dose is about 30
mg;
[0369] the first dose about 33 mg and the second dose is about 33
mg;
[0370] the first dose about 36 mg and the second dose is about 36
mg; and
[0371] the first dose about 39 mg and the second dose is about 39
mg.
[0372] In certain embodiments:
[0373] the first dose about 6 mg and the second dose is about 6
mg;
[0374] the first dose about 9 mg and the second dose is about 9
mg;
[0375] the first dose about 12 mg and the second dose is about 12
mg;
[0376] the first dose about 15 mg and the second dose is about 15
mg;
[0377] the first dose about 18 mg and the second dose is about 18
mg;
[0378] the first dose about 21 mg and the second dose is about 21
mg; and
[0379] the first dose about 24 mg and the second dose is about 24
mg.
[0380] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg. In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for subjects concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0381] In certain embodiments, the chorea control is improved by a
reduction of at least 0.5 points on the Total Maximal Chorea (TMC)
score. In certain embodiments, the reduction in TMC score is at
least 1 point. In certain embodiments, the reduction in TMC score
is at least 1.5 points. In certain embodiments, the reduction in
TMC score is at least 2.0 points. In certain embodiments, the
reduction in TMC score is at least 2.5 points. In certain
embodiments, the improvement is over a pre-treatment, "baseline"
TMC score of at least 8.0. In certain embodiments, the improvement
is over a pre-treatment, "baseline" TMC score of at least 10.0. In
certain embodiments, the improvement is over a pre-treatment,
"baseline" TMC score of at least 12.0. In certain embodiments, the
improvement is over a pre-treatment, "baseline" TMC score of at
least 12.7. In certain embodiments, the improvement is over a
pre-treatment, "baseline" TMC score of at least 14.0.
[0382] In certain embodiments, chorea is reduced by at least 10%.
In certain embodiments, chorea is reduced by at least 15%. In
certain embodiments, chorea is reduced by at least 20%.
[0383] In certain embodiments, motor function is improved.
[0384] In certain embodiments, motor function is improved by a
reduction of at least 1 point on the Total Motor Score (TMS). In
certain embodiments, the reduction in TMS score is at least 2
points. In certain embodiments, the reduction in TMS score is at
least 3 points. In certain embodiments, the reduction in TMS score
is at least 4 points.
[0385] In certain embodiments, dystonia is improved. In certain
embodiments, gait is improved. In certain embodiments, postural
instability is alleviated. In certain embodiments, treatment
reduces the symptoms of parkinsonism.
[0386] In certain embodiments, the treatment does not worsen the
subject's balance. In certain embodiments, the treatment improves
balance.
[0387] In certain embodiments, the subject is much improved on the
PGIC scale. In certain embodiments, the subject is very much
improved on the PGIC scale. In certain embodiments, the subject is
much improved on the CGIC scale. In certain embodiments, the
subject is very much improved on the CGIC scale. In certain
embodiments, the subject is much improved on the PGIC and CGIC
scales. In certain embodiments, the subject is very much improved
on the PGIC and CGIC scales.
[0388] In certain embodiments, the treatment improves physical
functioning. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale. In certain embodiments, the subject's physical
functioning is improved as measured by the SF-36 physical
functioning scale from baseline. In certain embodiments, the
subject's physical functioning is improved as measured by the SF-36
physical functioning scale compared to untreated subjects.
[0389] In certain embodiments, the treatment improves
swallowing.
[0390] In certain embodiments, treatment causes no significant
increase in insomnia, depression, anxiety, agitation, suicidal
ideation, akathisia, irritability, or fatigue.
[0391] In certain embodiments, treatment causes no significant
parkinsonism or dysphagia.
[0392] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0393] Also provided are embodiments wherein any embodiment above
in paragraphs [0175]-[0196] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine, or a VMAT2
inhibitor, for improving motor function in a subject with
Huntington's disease, tardive dyskinseia, or Tourette syndrome, as
set forth herein or in any of the embodiments above in paragraphs
[0175]-[0196] above. Also provided is the use of deutetrabenazine,
or a VMAT2 inhibitor, in the manufacture of a medicament for
improving motor function in a subject with Huntington's disease,
tardive dyskinseia, or Tourette syndrome, as set forth herein or in
any of the embodiments above in paragraphs [0175]-[0196] above.
Also provided is a composition comprising deutetrabenazine, or a
VMAT2 inhibitor, for use in improving motor function in a subject
with Huntington's disease, tardive dyskinseia, or Tourette
syndrome, as set forth herein or in any of the embodiments above in
paragraphs [0175]-[0196] above.
[0394] Also provided is a method of reducing motor or phonic tics
in a subject with Tourette syndrome, comprising the administration
of about a daily amount of deutetrabenazine.
[0395] In certain embodiments, the tics are motor tics.
[0396] In certain embodiments, the tics are phonic tics.
[0397] In certain embodiments, the subject is between 6 and 16
years of age. In certain embodiments, the subject is between 12 and
18 years of age. In certain embodiments, the subject is between 6
and 18 years of age.
[0398] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 48 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
and about 48 mg. In certain embodiments, the daily amount of
deutetrabenazine administered is less than or equal to about 48 mg,
or less than or equal to about 36 mg for subjects concurrently
receiving a strong CYP2D6 inhibitor. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from fluoxetine, paroxetine,
bupropion, quinidine, cinacalcet, and ritonavir. In certain
embodiments, the strong CYP2D6 inhibitor is chosen from paroxetine,
fluoxetine, and bupropion.
[0399] In certain embodiments, the daily amount of deutetrabenazine
is administered with food.
[0400] In certain embodiments, the daily amount of deutetrabenazine
is split into at least two doses.
[0401] In certain embodiments, the daily amount of deutetrabenazine
is administered in two equal doses, consisting of a first dose and
a second dose.
[0402] In certain embodiments, the motor or phonic tics are reduced
.gtoreq.25% as measured by the Total Tic Score of the Yale Global
Tic Severity Scale.
[0403] In certain embodiments, the motor or phonic tics are reduced
by 2 or more points on the Tourette Syndrome Clinical Global
Impression (TS-CGI).
[0404] In certain embodiments, the motor or phonic tics are reduced
by 1 or more points on the Tourette Syndrome Patient Global
Impression of severity (TS-PGIS). In certain embodiments, the motor
or phonic tics are reduced by 2 or more points on the Tourette
Syndrome Patient Global Impression of severity (TS-PGIS).
[0405] In certain embodiments, the reduction is from baseline to at
least two weeks.
[0406] In certain embodiments, the reduction is from baseline to at
least four weeks. In certain embodiments, the reduction is from
baseline to at least eight weeks. In certain embodiments, the
reduction is from baseline to at least twelve weeks.
[0407] Also provided are embodiments wherein any embodiment above
in paragraphs [0198]-[0211] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine, or a VMAT2
inhibitor, for reducing motor or phonic tics in a subject with
Tourette syndrome, as set forth herein or in any of the embodiments
above in paragraphs [0198]-[0211] above. Also provided is the use
of deutetrabenazine, or a VMAT2 inhibitor, in the manufacture of a
medicament for reducing motor or phonic tics in a subject with
Tourette syndrome, as set forth herein or in any of the embodiments
above in paragraphs [0198]-[0211] above. Also provided is a
composition comprising deutetrabenazine, or a VMAT2 inhibitor, for
use in reducing motor or phonic tics in a subject with Tourette
syndrome, as set forth herein or in any of the embodiments above in
paragraphs [0198]-[0211] above.
[0408] Also provided is a method of reducing motor and phonic tics
in a subject with Tourette syndrome, comprising the administration
of about a daily amount of deutetrabenazine.
[0409] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 48 mg. In certain embodiments, the daily
amount of deutetrabenazine is between 6 and 48 mg. In certain
embodiments, the daily amount of deutetrabenazine is chosen from
about 6 mg, about 12 mg, about 18 mg, about 24 mg, about 30 mg,
about 36 mg, about 42 mg, and about 48 mg. In certain embodiments,
the daily amount of deutetrabenazine administered is less than or
equal to about 48 mg, or less than or equal to about 36 mg for
subjects concurrently receiving a strong CYP2D6 inhibitor. In
certain embodiments, the strong CYP2D6 inhibitor is chosen from
fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, and
ritonavir. In certain embodiments, the strong CYP2D6 inhibitor is
chosen from paroxetine, fluoxetine, and bupropion.
[0410] In certain embodiments, the daily amount of deutetrabenazine
is administered with food.
[0411] In certain embodiments, the daily amount of deutetrabenazine
is split into at least two doses.
[0412] In certain embodiments, the daily amount of deutetrabenazine
is administered in two equal doses, consisting of a first dose and
a second dose.
[0413] In certain embodiments, the subject is between 6 and 16
years of age. In certain embodiments, the subject is between 12 and
18 years of age. In certain embodiments, the subject is between 6
and 18 years of age.
[0414] In certain embodiments, the motor and phonic tics are
reduced .gtoreq.25% as measured by the Total Tic Score of the Yale
Global Tic Severity Scale.
[0415] In certain embodiments, the motor or phonic tics are reduced
by 2 or more points on the Tourette Syndrome Clinical Global
Impression.
[0416] In certain embodiments, the reduction is from baseline to at
least two weeks. In certain embodiments, the reduction is from
baseline to at least four weeks. In certain embodiments, the
reduction is from baseline to at least eight weeks. In certain
embodiments, the reduction is from baseline to at least twelve
weeks.
[0417] In certain embodiments, the deutetrabenazine is a plus
isomeric form of deutetrabenazine. In certain embodiments, the plus
isomeric form of deutetrabenazine is an alpha isomer.
[0418] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0419] Also provided are embodiments wherein any embodiment above
in paragraphs [0213]-[0223] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine, or a VMAT2
inhibitor, for reducing motor and phonic tics in a subject with
Tourette syndrome, as set forth herein or in any of the embodiments
above in paragraphs [0213]-[0223] above. Also provided is the use
of deutetrabenazine, or a VMAT2 inhibitor, in the manufacture of a
medicament for reducing motor and phonic tics in a subject with
Tourette syndrome, as set forth herein or in any of the embodiments
above in paragraphs [0213]-[0223] above. Also provided is a
composition comprising deutetrabenazine, or a VMAT2 inhibitor, for
use in reducing motor and phonic tics in a subject with Tourette
syndrome, as set forth herein or in any of the embodiments above in
paragraphs [0213]-[0223] above.
[0420] Also provided is a method of reducing tic severity as
measured by the subject's Tourette Syndrome Patient Global
Impression of Severity (TS-PGIS) in a subject with Tourette
syndrome, comprising the administration of about a daily amount of
deutetrabenazine. In certain embodiments, the method comprises: a)
administering a daily amount of deutetrabenazine; and b) at least
once every 4 weeks, assessing tic severity using the TS-PGIS. In
further embodiments, the method additionally comprises: c) after
assessing tic severity using the TS-PGIS, if the daily amount of
deutetrabenazine is tolerable, increasing the daily amount of
deutetrabenazine by at least 6 mg/day; d) repeating steps b) and c)
until TS-PGIS is not further reduced or the daily amount of the
deutetrabenazine is tolerated; and e) if any subsequent amount is
not tolerated, decreasing the daily amount of deutetrabenazine
downward by 6 mg/day.
[0421] In certain embodiments, the tics are motor tics.
[0422] In certain embodiments, the tics are phonic tics.
[0423] In certain embodiments, the subject is between 6 and 16
years of age. In certain embodiments, the subject is between 12 and
18 years of age. In certain embodiments, the subject is between 6
and 18 years of age.
[0424] In certain embodiments, the daily amount of deutetrabenazine
is between 6 and 48 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg. In certain embodiments, the daily amount of deutetrabenazine
is administered with food.
[0425] In certain embodiments, tic severity is assessed using the
TS-PGIS at least every two weeks. In certain embodiments, tic
severity is assessed using the TS-PGIS at least weekly. In certain
embodiments, tic severity is assessed using the TS-PGIS at least
monthly. In certain embodiments, tic severity is assessed using the
TS-PGIS at least every three months.
[0426] In certain embodiments, the daily amount of deutetrabenazine
is split into two doses.
[0427] In certain embodiments, the reduction is from baseline to at
least two weeks. In certain embodiments, the reduction is from
baseline to at least four weeks. In certain embodiments, the
reduction is from baseline to at least eight weeks. In certain
embodiments, the reduction is from baseline to at least twelve
weeks.
[0428] In certain embodiments, the deutetrabenazine is a plus
isomeric form of deutetrabenazine. In certain embodiments, the plus
isomeric form of deutetrabenazine is an alpha isomer.
[0429] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0430] Also provided are embodiments wherein any embodiment above
in paragraphs [0213]-[0234] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine for
reducing tic severity as measured by the subject's Tourette
Syndrome Patient Global Impression of Severity (TS-PGIS), as set
forth herein or in any of the embodiments above in paragraphs
[0213]-[0234] above. Also provided is the use of deutetrabenazine
in the manufacture for reducing tic severity as measured by the
subject's Tourette Syndrome Patient Global Impression of Severity
(TS-PGIS), as set forth herein or in any of the embodiments above
in paragraphs [0213]-[0234] above. Also provided is a composition
comprising deutetrabenazine for use in reducing tic severity as
measured by the subject's Tourette Syndrome Patient Global
Impression of Severity (TS-PGIS), as set forth herein or in any of
the embodiments above in paragraphs [0213]-[0234] above.
[0431] Also provided is a method of maintaining control of abnormal
involuntary movements in a human subject with a movement disorder,
comprising administering to the subject a therapeutically effective
daily amount of deutetrabenazine for a period of time sufficient to
do one or more of the following: reduce chorea by at least 10%;
improve motor function by at least 10%; improve physical
functioning; improve swallowing; improve balance; reduce abnormal
involuntary movements in subjects with tardive dyskinesia; reduce
motor tics; reduce vocal/phonic tics; reduce motor and vocal/phonic
tics; reduce impairment in subjects with Tourette syndrome; reduce
the severity of Tourette syndrome; reduce the patient global
impression of severity in subjects with Tourette Syndrome; and much
or very much improve the subject's patient of clinical global
impression of change.
[0432] In certain embodiments, the disorder is chosen from
Huntington's disease, tardive dyskinesia, and Tourette
syndrome.
[0433] In certain embodiments, or improvement in each of the
endpoints above is measured as follows: reduction in chorea is
measured by the Unified Huntington's Disease Rating Scale (UHDRS)
or a subscale thereof; reduction in chorea is measured by the Total
Maximal Chorea (TMC) score of the UHDRS; improvement in motor
function is measured by the Total Motor Score (TMS) score of the
UHDRS; improvement in physical functioning is measured by the SF-36
physical functioning scale; improvement in swallowing is measured
by the Swallowing Disturbance Questionnaire (SDQ); improvement in
balance is measured by the Berg Balance Test (BBT); reduction in
abnormal involuntary movements in subjects with tardive dyskinesia
is measured by the AIMS; reduction in motor tics in subjects with
Tourette Syndrome is measured by the MTSS of the YGTSS; reduction
in vocal/phonic tics in subjects with Tourette Syndrome is measured
by the VTSS of the YGTSS; reduction in total (motor and
vocal/phonic) tics is measured by the TTS of the YGTSS; reduction
in impairment is measured by the Impairment score of the YGTSS;
reduction in the severity of Tourette syndrome is measured by the
the global severity score of the YGTSS; and reduction in patient
global impression of severity in subjects with Tourette Syndrome is
measured by the TS-PGIS.
[0434] In certain embodiments, the daily amount of deutetrabenazine
is about 6 mg to about 78 mg. In certain embodiments, the daily
amount of deutetrabenazine is chosen from about 6 mg, about 12 mg,
about 18 mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg,
about 48 mg, about 54 mg, about 60 mg, about 66 mg, about 72 mg,
and about 78 mg. In certain embodiments, the daily amount of
deutetrabenazine is chosen from about 6 mg, about 12 mg, about 18
mg, about 24 mg, about 30 mg, about 36 mg, about 42 mg, and about
48 mg. In certain embodiments, the daily amount of deutetrabenazine
administered is less than or equal to about 48 mg, or less than or
equal to about 36 mg for subjects concurrently receiving a strong
CYP2D6 inhibitor. In certain embodiments, the strong CYP2D6
inhibitor is chosen from fluoxetine, paroxetine, bupropion,
quinidine, cinacalcet, and ritonavir. In certain embodiments, the
strong CYP2D6 inhibitor is chosen from paroxetine, fluoxetine, and
bupropion.
[0435] In certain embodiments, the sufficient period of time is at
least four weeks. In certain embodiments, the sufficient period of
time is at least eight weeks. In certain embodiments, the
sufficient period of time is at least twelve weeks.
[0436] In certain embodiments, the reduction or improvement in the
relevant measure or measures is by at least 10% over baseline. In
certain embodiments, the reduction or improvement in the relevant
measure or at least one of the measures is by at least 20% over
baseline. In certain embodiments, the reduction or improvement in
the relevant measure or at least one of the measures is by at least
30% over baseline. In certain embodiments, the reduction or
improvement in the relevant measure or at least one of the measures
is by at least 40% over baseline. In certain embodiments, the
reduction or improvement in the relevant measure or at least one of
the measures is by at least 50% over baseline.
[0437] In certain embodiments, the disorder is Huntington's
disease. In certain embodiments, the abnormal involuntary movement
is chorea associated with Huntington's disease.
[0438] In certain embodiments, the disorder is tardive
dyskinesia.
[0439] In certain embodiments, the disorder is Tourette syndrome.
In certain embodiments, the abnormal involuntary movement is a tic
associated with Tourette syndrome.
[0440] In certain embodiments, the deutetrabenazine is a plus
isomeric form of deutetrabenazine. In certain embodiments, the plus
isomeric form of deutetrabenazine is an alpha isomer.
[0441] In certain embodiments, the treatment does not significantly
prolong the QT interval. In certain embodiments, the treatment does
not significantly change the QTcF value. In certain embodiments,
the maximal increases in QTcF is less than 5 ms.
[0442] Also provided are embodiments wherein any embodiment above
in paragraphs [0238]-[0246] above may be combined with any one or
more of these embodiments, provided the combination is not mutually
exclusive. Also provided is the use of deutetrabenazine for
maintaining control of abnormal involuntary movements in a human
subject with a movement disorder, as set forth herein or in any of
the embodiments above in paragraphs [0238]-[0246] above. Also
provided is the use of deutetrabenazine in the manufacture of a
medicament for maintaining control of abnormal involuntary
movements in a human subject with a movement disorder, as set forth
herein or in any of the embodiments above in paragraphs
[0238]-[0246] above. Also provided is a composition comprising
deutetrabenazine for maintaining control of abnormal involuntary
movements in a human subject with a movement disorder, as set forth
herein or in any of the embodiments above in paragraphs
[0238]-[0246] above.
Compositions
[0443] Tetrabenazine (Nitoman, Xenazine, Ro 1-9569),
1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quin-
oline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor.
Tetrabenazine is commonly prescribed for the treatment of
Huntington's disease (Savani et al., Neurology 2007, 68(10), 797;
and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1),
7-17). Tetrabenazine is subject to extensive oxidative metabolism,
including O-demethylation of the methoxy groups, as well as
hydroxylation of the isobutyl group (Schwartz et al., Biochem.
Pharmacol., 1966, 15, 645-655). Adverse effects associated with the
administration of tetrabenazine include neuroleptic malignant
syndrome, drowsiness, fatigue, nervousness, anxiety, insomnia,
agitation, confusion, orthostatic hypotension, nausea, dizziness,
depression, and Parkinsonism.
##STR00001##
Deuterium Enriched Tetrabenazine Analogues
[0444] d.sub.6-Tetrabenazine (equivalently, deutetrabenazine,
SD-809, or DTBZ) is a deuterated analog of tetrabenazine currently
under clinical development. U.S. Pat. No. 8,524,733, US
20100130480, and US 20120003330.
##STR00002##
(RR,
SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylprop-
yl)-2H-benzo[a]quinolizin-2-one
[0445] In all of the the methods and compositions disclosed herein
using deutetrabenazine, the deutetrabenazine may be administered or
formulated as part of a pharmaceutical composition wherein the
composition has deuterium enrichment of at least 90% at each of the
positions designated D. In certain embodiments, the composition has
deuterium enrichment of at least 95% at each of the positions
designated D. In certain embodiments, the composition has deuterium
enrichment of at least 98% at each of the positions designated
D.
[0446] In humans, as shown below, d.sub.6-tetrabenazine is rapidly
and extensively converted in the liver (similarly to
non-isotopically enriched tetrabenazine) to major, active
dihydrotetrabenazine (HTBZ) metabolites referred to as
d.sub.6-.alpha.-HTBZ and d.sub.6-.beta.-HTBZ (as a mixture of the +
and - isomers) which have the structures below (+ isomers shown).
These metabolites are believed to drive clinical efficacy.
##STR00003##
[0447] Deuterium substituted tetrabenazines include, in addition to
deutetrabenazine disclosed above, compounds as disclosed in U.S.
Pat. No. 8,524,733, US 20100130480, and US 20120003330, and
PCT/US2014/066740, filed Nov. 14, 2014. Examples of such compounds
are given in the following structural formulas.
[0448] In certain embodiments of the present invention, compounds
have structural Formula I:
##STR00004## [0449] or a salt, solvate, or prodrug thereof,
wherein: [0450] R.sub.1-R.sub.27 are independently selected from
the group consisting of hydrogen and deuterium; [0451] and [0452]
at least one of R.sub.1-R.sub.27 is deuterium.
[0453] In certain embodiments, Formula I can include a single
enantiomer, a mixture of the (+)-enantiomer and the (-)-enantiomer,
a mixture of about 90% or more by weight of the (-)-enantiomer and
about 10% or less by weight of the (+)-enantiomer, a mixture of
about 90% or more by weight of the (+)-enantiomer and about 10% or
less by weight of the (-)-enantiomer, an individual diastereomer,
or a mixture of diastereomers thereof.
[0454] In certain embodiments of the present invention, compounds
have structural Formula II:
##STR00005## [0455] or a salt thereof, wherein: [0456]
R.sub.28-R.sub.46 and R.sub.48-R.sub.56 are independently selected
from the group consisting of hydrogen and deuterium; [0457]
R.sub.47 is selected from the group consisting of hydrogen,
deuterium, --C(O)O-alkyl and --C(O)--C.sub.1-6alkyl, or a group
cleavable under physiological conditions, wherein said alkyl or
C.sub.1-6alkyl is optionally substituted with one or more
substituents selected from the group consisting of --NH--C(NH)NH2,
--CO.sub.2H, --CO.sub.2alkyl, --SH, --C(O)NH.sub.2, --NH.sub.2,
phenyl, --OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any
R.sub.46 substituent is further optionally substituted with
deuterium; and [0458] at least one of R.sub.28-R.sub.56 is
deuterium or contains deuterium.
[0459] In certain embodiments, the compounds of Formula II have
alpha stereochemistry.
[0460] In further embodiments, the compounds of Formula II have
beta stereochemistry.
[0461] In yet further embodiments, the compounds of Formula II are
a mixture of alpha and beta stereoisomers. In yet further
embodiments, the ratio of alpha/beta stereoisomers is at least
100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1,
at least 4:1, at least 3:1, or at least 2:1. In yet further
embodiments, the ratio of beta/alpha stereoisomers is at least
100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1,
at least 4:1, at least 3:1, or at least 2:1.
[0462] In certain embodiments, if R.sub.50-R.sub.56 are deuterium,
at least one of R.sub.1-R.sub.49 is deuterium.
[0463] In certain embodiments of the present invention, compounds
have structural Formula III:
##STR00006## [0464] or a salt, stereoisomer, or racemic mixture
thereof, wherein: [0465] R.sub.57-R.sub.83 are independently
selected from the group consisting of hydrogen and deuterium;
[0466] and [0467] at least one of R.sub.57-R.sub.83 is
deuterium.
[0468] In certain embodiments of the present invention, compounds
have structural Formula IV:
##STR00007## [0469] or a salt, diastereomer, or mixture of
diastereomers thereof, wherein: [0470] R.sub.84-R.sub.110 are
independently selected from the group consisting of hydrogen and
deuterium; and [0471] at least one of R.sub.84-R.sub.110 is
deuterium.
[0472] Deuterium substituted tetrabenazine metabolites include, in
addition to d.sub.6-.alpha.-HTBZ and d.sub.6-.beta.-HTBZ disclosed
above, compounds disclosed in of the following structural
formulas.
[0473] The terms "alpha-dihydrotetrabenazine",
".alpha.-dihydrotetrabenazine", or the terms "alpha" or "alpha
stereoisomer" or the symbol ".alpha." as applied to
dihydrotetrabenazine refers to either of the dihydrotetrabenazine
stereoisomers having the structural formulas shown below, or a
mixture thereof:
##STR00008##
[0474] The terms "alpha" or "alpha stereoisomer" or the symbol
".alpha." as applied to a compound of Formula II refers to either
of the stereoisomers of compounds of Formula II shown below, or a
mixture thereof:
##STR00009##
[0475] The terms "beta-dihydrotetrabenazine",
".beta.-dihydrotetrabenazine", or the terms "beta" or "beta
stereoisomer" or the symbol ".beta." as applied to
dihydrotetrabenazine refers to either of the dihydrotetrabenazine
stereoisomers having the structural formulas shown below, or a
mixture thereof:
##STR00010##
[0476] The terms "beta" or "beta stereoisomer" or the symbol
".beta." as applied to a compound of Formula II refers to either of
the stereoisomers of compounds of Formula II shown below, or a
mixture thereof:
##STR00011##
[0477] The terms "3S,11bS enantiomer" or the term "3R,11bR
enantiomer" refers to either of the d.sub.6-tetrabenazine M4
metabolite stereoisomers having the structural formulas shown
below:
##STR00012##
[0478] In certain embodiments, a chemical structure may be drawn as
either the 3S,11bS enantiomer or the 3R,11bR enantiomer, but the
text of the specification may indicate that the 3S,11bS enantiomer,
the 3R,11bR enantiomer, a racemic mixture thereof, or all of the
foregoing may be intended to be described.
[0479] The terms "(3S,11bS)-enantiomer" or "(3R,11bR)-enantiomer"
or the as applied to a compound of Formula I refers to either of
the stereoisomers of compounds of Formula III shown below:
##STR00013##
[0480] The term "mixture of diastereomers" refers to either of the
d.sub.6-tetrabenazine M1 metabolite stereoisomers having the
structural formulas shown below:
##STR00014##
[0481] In certain embodiments, a chemical structure may be drawn as
one of the diastereomers shown above, but the text of the
specification may indicate that each individual diastereomer or a
mixture thereof, or all of the foregoing may be intended to be
described.
[0482] The term "mixture of diastereomers" as applied to a compound
of Formula IV refers to a mixture of the stereoisomers of compounds
of Formula IV shown below:
##STR00015##
[0483] Additional deuterium enriched tetrabenazine analogues
include analogs of valbenazine. Valbenazine (NBI-98854, CAS
#1025504-59-9,
(S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyr-
ido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate) is a VMAT2
inhibitor. Valbenazine is currently under investigation for the
treatment of movement disorders including tardive dyskinesia. WO
2008058261; WO 2011153157; and U.S. Pat. No. 8,039,627.
Valbenazine, a valine ester of (+)-.alpha.-dihydrotetrabenazine, in
humans is slowly hydrolyzed to (+)-.alpha.-dihydrotetrabenazine
which is an active metabolite of tetrabenazine which is currently
used for the treatment of Huntington's disease. Savani et al.,
Neurology 2007, 68(10), 797; and Kenney et al., Expert Review of
Neurotherapeutics 2006, 6(1), 7-17.
##STR00016##
[0484] Dihydrotetrabenazine, formed by hydrolysis of the valine
ester of valbenazine, is subject to extensive oxidative metabolism,
including O-demethylation of the methoxy groups, as well as
hydroxylation of the isobutyl group (Schwartz et al., Biochem.
Pharmacol., 1966, 15, 645-655). Adverse effects associated
potentially associated with the administration of valbenazine
include neuroleptic malignant syndrome, drowsiness, fatigue,
nervousness, anxiety, insomnia, agitation, confusion, orthostatic
hypotension, nausea, dizziness, depression, and Parkinsonism.
[0485] Deuterium-substituted analogues of valbenazine include those
as disclosed in WO2014120654. Examples of such compounds are given
in the Formulas below.
[0486] In certain embodiments of the present invention, compounds
have structural Formula I:
##STR00017##
or a salt thereof, wherein:
[0487] R.sub.1-R.sub.19 and R.sub.21-R.sub.29 are independently
selected from the group consisting of hydrogen and deuterium;
[0488] R.sub.20 is selected from the group consisting of hydrogen,
deuterium, --C(O)O-alkyl and --C(O)--C.sub.1-6alkyl, or a group
cleavable under physiological conditions, wherein said alkyl or
C.sub.1-6alkyl is optionally substituted with one or more
substituents selected from the group consisting of --NH--C(NH)NH2,
--CO.sub.2H, --CO.sub.2alkyl, --SH, --C(O)NH.sub.2, --NH.sub.2,
phenyl, --OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any
R.sub.20 substituent is further optionally substituted with
deuterium; and
[0489] at least one of R.sub.1-R.sub.29 is deuterium or contains
deuterium.
[0490] In certain embodiments, the compounds of Formula V have
(+)-alpha stereochemistry.
[0491] In certain embodiments, the compounds of Formula V have
(-)-alpha stereochemistry.
[0492] In further embodiments, the compounds of Formula V have
(+)-beta stereochemistry.
[0493] In further embodiments, the compounds of Formula V have
(-)-beta stereochemistry.
[0494] In yet further embodiments, the compounds of Formula I are a
mixture of alpha and beta stereoisomers. In yet further
embodiments, the ratio of alpha/beta stereoisomers is at least
100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1,
at least 4:1, at least 3:1, or at least 2:1. In yet further
embodiments, the ratio of beta/alpha stereoisomers is at least
100:1, at least 50:1, at least 20:1, at least 10:1, at least 5:1,
at least 4:1, at least 3:1, or at least 2:1.
[0495] In certain embodiments, disclosed herein is a compound of
structural Formula VI:
##STR00018##
or a salt or stereoisomer thereof, wherein:
[0496] R.sub.1-R.sub.19 and R.sub.21-R.sub.39 are independently
selected from the group consisting of hydrogen and deuterium;
[0497] at least one of R.sub.1-R.sub.19 and R.sub.21-R.sub.39 is
deuterium.
[0498] In certain embodiments of the present invention, compounds
have structural Formula VII:
##STR00019##
or a salt or stereoisomer thereof, wherein:
[0499] R.sub.20 is selected from the group consisting of
--C(O)O-alkyl and --C(O)--C.sub.1-6alkyl, or a group cleavable
under physiological conditions, wherein said alkyl or
C.sub.1-6alkyl is optionally substituted with one or more
substituents selected from the group consisting of --NH--C(NH)NH2,
--CO.sub.2H, --CO.sub.2alkyl, --SH, --C(O)NH.sub.2, --NH.sub.2,
phenyl, --OH, 4-hydroxyphenyl, imidazolyl, and indolyl, and any
R.sub.20 substituent is further optionally substituted with
deuterium.
[0500] The compounds as disclosed herein may also contain less
prevalent isotopes for other elements, including, but not limited
to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen.
Deuterium Kinetic Isotope Effect
[0501] Deuterium (D) is a naturally occurring, non-radioactive,
stable isotope of hydrogen (H), that contains both a proton and a
neutron in its nucleus. The presence of the neutron doubles the
mass of D when compared to H, which in turn increases the
vibrational frequency of the C-D covalent bond as compared to the
C--H covalent bond. An increase in the vibrational frequency of a
covalent bond results in an increase in the activation energy
required to break that bond, and consequentially an increase in the
bond strength. This increased covalent bond strength can in certain
instances alter the kinetics of the covalent bond cleavage
resulting in what is known as the Kinetic Isotope Effect (KIE).
Under certain specific conditions that involve various quantum
mechanical aspects of the covalent bond cleavage, the replacement
of a covalent C--H bond with a covalent C-D bond can result in a
meaningful deuterium KIE. A large deuterium KIE for a drug that is
a CYP450 substrate can in certain instances lead to an improvement
in the pharmacokinetic parameters of that drug, which can
potentially result in a differentiation between the deuterated and
the non-deuterated drugs. The covalent C-D bonds in
deutetrabenazine satisfy a number of chemical and biological
criteria which work in concert to provide a deuterium KIE that is
large enough to slow down the O-demethylation of the active
metabolites of deutetrabenazine as compared to tetrabenazine. It is
important to note that the magnitude of this deuterium KIE could
not have been predicted a priori, and hence it was not possible to
know ahead of time if the replacement of a C--H covalent bond in
tetrabenazine with a C-D covalent bond would have led to a
noticeable and/or improved biological difference.
[0502] Deutetrabenazine or d.sub.6-tetrabenazine is a VMAT2
inhibitor.
[0503] In the d.sub.6-tetrabenazine, six hydrogen atoms are
replaced with deuterium atoms as shown in foregoing figure. There
is substantial evidence that d.sub.6-tetrabenazine forms stable
covalent bonds, and that its trideuteromethyl group (--CD.sub.3) is
a covalently bound stable moiety with no distinctions or
qualifications of that bond as compared to a methyl group
(--CH.sub.3).
[0504] First, the covalent nature of the C-D bond can be
established by spectroscopic methods such as Infrared (IR)
Spectroscopy. The characteristic IR absorption of C-D stretches at
approximately 2000-2300 cm-1 (Miller and Corcelli, 2009) is often
used by researchers as site-specific and non-perturbative probes
for protein studies (Miller and Corcelli, 2009; Zimmermann et al.,
2011). d.sub.6-tetrabenazine has distinct IR absorptions at
2060-2250 cm-1 which are attributed to the C-D stretches. These
absorption bands are absent from the IR spectrum of the
non-deuterated form of tetrabenazine.
[0505] Second, d.sub.6-tetrabenazine is not a salt form of
tetrabenazine. The mass spectrum of deutetrabenazine displays the
protonated molecular ion at m/z 324.18 [M+1]. This agrees with the
predicted mass number of d.sub.6-tetrabenazine as an intact
molecule.
[0506] Third, deuterium atoms in d.sub.6-tetrabenazine do not
exchange with hydrogen under normal physiological conditions. The
pKa of non-conjugated aliphatic C--H bonds is in the range of
45-50, which means that at equilibrium, the ratio of dissociated to
non-dissociated species is less than 10-45. By comparison, the C--H
bonds of the methoxy groups of tetrabenazine, and by extension, the
C-D bonds of the methoxy groups of d.sub.6-tetrabenazine are even
less acidic, with a pKa value approaching 50. This means that one
would need to increase the pH of an aqueous solution to more than
45 before any of the deuterium atoms in deutetrabenazine can
potentially start exchanging with hydrogen atoms.
[0507] Finally, d.sub.6-tetrabenazine or deutetrabenazine has been
administered to humans in clinical studies, and subject to various
in vitro incubations with multiple enzymatic processes. The known
active metabolites as well as further downstream metabolites have
been monitored in vitro incubates and/or in human plasma by
LC/MS/MS methods. These metabolites have been synthesized and
confirmed to contain the expected trideuteromethyl groups
(--CD.sub.3), confirming that the covalent C-D bonds in
deutetrabenazine are stable and carried into the downstream
metabolites of deutetrabenazine. Deutetrabenazine has a
differentiated pharmacokinetics profile compared to
d.sub.0-tetrabenazine.
[0508] Due to the deuterium kinetic isotope effect (KIE), replacing
H with a D in a covalent C--H bond in a small molecule drug has the
potential to attenuate the metabolism of the drug (Baillie, 1981)
by requiring more energy for cleavage by enzymes such as cytochrome
P450 isozymes (CYP450). The magnitude of the deuterium KIE varies
depending on the nature of the C--H bond that is being broken and
whether the cleavage of that bond is the rate-limiting step in the
oxidative metabolism of the drug by a CYP isozyme.
[0509] By attenuating metabolism in this manner, elimination
half-life (t.sub.1/2), exposure (AUC [area under the plasma
level-time curve]), and peak plasma concentration (Cmax) may be
altered relative to the non-deuterated form of the drug (Kushner et
al., 1999; Baillie, 1981). The substitution of D for H at specific
positions in a drug has also the potential to attenuate the
breakdown of the deuterium containing metabolites of the deuterated
parent drug. Many deuterium substitutions of key oxidative
metabolic sites do not produce any effects; thus empirical data are
required to determine whether deuteration has potentially relevant
outcomes in vivo. Tetrabenazine contains numerous C--H covalent
bonds that are subject to oxidative metabolism by CYP450 enzymes.
For all of the foregoing reasons, a medicine with a longer
half-life may result in greater efficacy, better safety and
tolerability, improved quality of life and potential for cost
savings in the long term. Various deuteration patterns can be used
to (a) reduce or eliminate unwanted metabolites, (b) increase the
half-life of the parent drug, (c) decrease the number of doses
needed to achieve a desired effect, (d) decrease the amount of a
dose needed to achieve a desired effect, (e) increase the formation
of active metabolites, if any are formed, (f) decrease the
production of deleterious metabolites in specific tissues, and/or
(g) create a more effective drug and/or a safer drug for
polypharmacy, whether the polypharmacy be intentional or not. The
deuteration approach has demonstrated the ability to slow the
metabolism of tetrabenazine and attenuate interpatient
variability.
ABBREVIATIONS AND DEFINITIONS
[0510] To facilitate understanding of the disclosure, a number of
terms and abbreviations as used herein are defined below as
follows:
[0511] All publications and references cited herein are expressly
incorporated herein by reference in their entirety. However, with
respect to any similar or identical terms found in both the
incorporated publications or references and those explicitly put
forth or defined in this document, then those terms definitions or
meanings explicitly put forth in this document shall control in all
respects.
[0512] The singular forms "a," "an," and "the" may refer to plural
articles unless specifically stated otherwise.
[0513] When ranges of values are disclosed, and the notation "from
n1 . . . to n2" or "n1-n2" is used, where n1 and n2 are the
numbers, then unless otherwise specified, this notation is intended
to include the numbers themselves and the range between them. This
range may be integral or continuous between and including the end
values.
[0514] The term "and/or" when used in a list of two or more items,
means that any one of the listed items can be employed by itself or
in combination with any one or more of the listed items. For
example, the expression "A and/or B" is intended to mean either or
both of A and B, i.e. A alone, B alone or A and B in combination.
The expression "A, B and/or C" is intended to mean A alone, B
alone, C alone, A and B in combination, A and C in combination, B
and C in combination or A, B, and C in combination.
[0515] The term "about," as used herein when referring to a
measurable value such as an amount of a compound, dose, time,
temperature, and the like, is meant to encompass variations of 20%,
10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.
[0516] As used herein, the term "abnormal" refers to an activity or
feature that differs from a normal activity or feature.
[0517] As used herein, the term "abnormal muscular activity" refers
to muscular activity that differs from the muscular activity in a
healthy subject. The abnormal activity may be decreased or
increased in comparison to normal activity. An increase in muscular
activity can result in excessive abnormal movements, excessive
normal movements, or a combination of both.
[0518] The term "adverse event" ("AE") means any untoward medical
occurrence in a patient administered a drug, regardless of whether
it has a causal relationship with this treatment. An adverse event
can, therefore, be any unfavorable and unintended physical sign,
symptom, or laboratory parameter that develops or worsens in
severity during the course of this study, or significant worsening
of the disease under study or of any concurrent disease, whether or
not considered related to the study drug. A new condition or the
worsening of a pre-existing condition will be considered an adverse
event. Stable chronic conditions (such as arthritis) that are
present before study entry and do not worsen during this study will
not be considered adverse events. A mild AE is one which does not
limit the subject's activities; a moderate AE is one which causes
some limitation of usual activities; and a severe AE is one which
renders a subject unable to carry out usual activities.
[0519] A "treatment-related adverse event" is an adverse event
which, in a physician's or clinician's judgment, is related to the
drug administered. Such a determination should be understood to
often not reduce to a yes/no question, but may lie on a continuum
wherein it is more or less likely that the AE is treatment-related,
including the closeness of manifestation of the event to dosing,
the disappearance of the AE upon discontinuation or reduction in
dose of the drug, and the failure of other factors (e.g.,
preexisting conditions, environmental factors, etc.) to explain the
AE.
[0520] The term "CYP2D6 inhibitor" refers to a drug which is
inhibits CYP2D6, therefore making it unavailable to metabolize
other substrate compounds; co-administration of a drug metabolized
by CYP2D6 with a CYP2D6 inhibitor should be carried out with
caution and often at a reduced dosage, as the plasma concentration
of the drug will often be. CYP2D6 inhibitors include amiodarone,
celecoxib, chloroquine, chlorpromazine, cimetidine, citalopram,
clomipramine, codeine, deiavirdine, desipramine, dextroprpoxyphene,
diltiazem, doxorubicin, entacapone (high dose), fluoxetine,
fluphenazine, fluvaxamine, haloperidol, labetalol, lobeline,
lomustine, methadone, mibefradil, moclobemide, nortuloxeline,
paroxetine, perphenazine, propafenone, quinacrine, quinidine,
ranitidine, risperidone, ritonavir, serindole, sertraline,
thioridazine, valproic acid, venlafaxine, vinblastine, vincristine,
vinorelbine, and yohimbine. Strong CYP2D6 inhibitors include
fluoxetine, aroxetine, bupropion, quinidine, cinacalcet, and
ritonavir.
[0521] The term "degree" as used herein in reference to control of
abnormal muscular activity or abnormal involuntary movement (e.g.,
chorea) is meant to be synonymous with "level."
[0522] The term "disorder" as used herein is intended to be
generally synonymous, and is used interchangeably with, the terms
"disease", "syndrome", and "condition" (as in medical condition),
in that all reflect an abnormal condition of the human or animal
body or of one of its parts that impairs normal functioning, is
typically manifested by distinguishing signs and symptoms.
[0523] The terms "treat," "treating," and "treatment" are meant to
include alleviating or abrogating a disorder or one or more of the
symptoms associated with a disorder; or alleviating or eradicating
the cause(s) of the disorder itself. As used herein, reference to
"treatment" of a disorder is intended to include prevention.
[0524] The terms "prevent," "preventing," and "prevention" refer to
a method of delaying or precluding the onset of a disorder; and/or
its attendant symptoms, barring a subject from acquiring a disorder
or reducing a subject's risk of acquiring a disorder.
[0525] The terms "tolerable" and "tolerability" refer to that
amount of deuterium-substituted tetrabenazine (e.g.,
deutetrabenazine) or other drug (e.g., deuterium-substituted VMAT
inhibitor, or valbenazine) which produces low rates of adverse
events such as somnolence, irritability, fatigue, vomiting and
nausea in patients and where the adverse events do not lead to dose
reduction of the deuterium substituted tetrabenazine or other drug,
suspension of the deuterium substituted tetrabenazine or other
drug, or withdrawal of the drug deuterium substituted tetrabenazine
or other drug. The deuterium substituted tetrabenazine is also
considered tolerable if any underlying symptoms such as depression,
anxiety, suicidality, parkinsonism in patients having diseases or
conditions, such as Huntington's disease, tardive dyskinesia or
Tourette syndrome, are not worsened. Tolerable and tolerability
shall also refer to that amount of deutetrabenazine (or other drug,
if applicable) which does not necessitate a downward adjustment in
regular (e.g., daily) dose, or a suspension of dose, for example
due to adverse effects. A tolerable amount may vary from between
subjects, and also within a subject over the course of a disease or
course of treatment.
[0526] The term "adequate" as used herein in reference to control
of abnormal muscular activity or abnormal involuntary movement
(e.g., chorea) in a subject refers a level of control which is
observable and satisfactory to the subject. The clinician,
investigator, in consultation with the subject, will determine when
an adequate level of control of abnormal muscular activity or
abnormal involuntary movement (e.g., chorea) has been achieved.
Typically, the adequacy of a level of control of abnormal muscular
activity or abnormal involuntary movement provided by an amount of
a drug will be affected by the tolerability of that amount, and
will often be the maximum tolerated amount which yields an
observable increase in control (the "optimal" amount). The amount
of deutetrabenazine may be increased on a weekly basis until there
is adequate control of chorea, the subject experiences a protocol
defined "clinically significant" adverse event (defined as related
to study medication and either a) moderate or severe in intensity
or b) meets the criteria for a Serious Adverse Event (SAE), or the
maximal allowable dose is reached. An adequate level may vary from
between subjects, and also within a subject over the course of a
disease or course of treatment.
[0527] The phrases "improve," "improved by," "reduce," "reduced
by," and the like, used in reference to a level, degree, or amount
by which some quality is reduced, improved, etc. in a subject or
subjects by treatment with a compound, is meant to be in comparison
to an untreated subject or subjects. Alternatively, if explicitly
so stated, these phrases may be in comparison to a subject or
subjects treated with a standard of care. Such measures may be made
by reference to a relevant scale or assessment known in the art
(see, e.g., examples provided herein of disorder-control and/or
disorder-eradication endpoint scales, and Likert scales).
[0528] The term "abnormal involuntary movement," as used herein,
includes involuntary movements associated with or caused by
movement disorders.
[0529] The term "subject" refers to an animal, including, but not
limited to, a primate (e.g., human, monkey, chimpanzee, gorilla,
and the like), rodents (e.g., rats, mice, gerbils, hamsters,
ferrets, and the like), lagomorphs, swine (e.g., pig, miniature
pig), equine, canine, feline, and the like. The terms "subject" and
"patient" are used interchangeably herein in reference, for
example, to a mammalian subject, such as a human patient.
[0530] The GTS-QOL consists of two parts. The first part is
typically a twenty-seven question assessment of various aspects of
how tics affect the subject's life, each to be rated on a
five-choice scale of no problem, slight problem, moderate problem,
marked problem, or severe problem. Subscales combining some of
these aspects can be focused upon, such as, e.g., the
physical/activities of daily living (ADL) subscale. The second part
is a simple rating of the subject's life satisfaction, where 100 is
extremely satisfied and 0 is extremely dissatisfied.
[0531] SF-36 Physical Functioning Score. The SF-36 is a short-form
health survey with 36 questions used to evaluate health-related
quality of life (Ware, 1996). The SF-36 has been useful in
comparing specific populations and comparing the relative burden of
various diseases. The SF-36 has been evaluated in HD patients and
shown to have robust construct validity and test-retest reliability
and was also able to discriminate from age-matched controls and
normative data on the 10-item physical functioning scale (Ho,
2004). While the entire SF-36 was administered in this study, the
physical functioning scale (also known as the PF-10) was analyzed
as a key secondary endpoint. The physical functioning scale is a
10-item subset of the SF-36 which examines a subject's perceived
health-related limitations with physical activities. The SF-36
physical functioning score is a 10-item scale where subjects rate
their ability to perform routine physical activities such as
walking, climbing stairs, bathing, or dressing. Given the potential
for chorea to interfere with basic motor skills, gait, and walking
it is not unexpected that subjects with more impaired function
would experience greater benefit on this measure.
[0532] The Tourette Syndrome Patient Global Impression of Severity
(TS-PGIS) is a novel five-point scale in which 1 indicates no tics,
2 indicates mild tics (not distressing, noticeable, or interfering
with daily life), 3 indicates moderate (can be distressing,
noticeable, and sometimes interfering with daily life), 4 indicates
marked (very distressing, noticeable, and interfering with daily
life), and 5 indicates severe (severely distressing, always
noticeable, and preventing of most daily activities).
[0533] The Tic-Free Interval is a five-point scale in which 1
indicates an interval of at least one day since the last tic, 2
indicates an interval of between 6 hours to less than one day since
the last tic, 3 indicates an interval of between one hour and less
than 6 hours since the last tic, 4 indicates an interval of between
five minutes to less than one hour since the last tic, and 5
indicates less than five minutes since the last tic.
[0534] The TS-CGI is a seven-point scale scored by the clinician,
in which 1 indicates normal or no tics, 2 indicates tics may or may
not be present, 3 indicates mild, observable motor and/or phonic
tics that may or may not be noticed, would not call attention to
the individual, and are associated with no distress or impairment,
4 indicates moderate, observable motor and/or phonic tics that
would always be noticed, would call attention to the individual,
and may be associated with some distress or impairment, 5 indicates
marked, exaggerated motor and/or phonic tics that are disruptive,
would always call attention to the individual, and are always
associated with significant distress or impairment, 6 indicates
severe, extremely exaggerated motor and/or phonic tics that are
disruptive, would always call attention to the individual, and are
associated with injury or inability to carry out daily functions,
and 7 indicates extreme, incapacitating tics.
[0535] The YGTSS is a comprehensive evaluation of various aspects
and severity of motor and phonic tics. In one aspect, each of five
categories--number, frequency, intensity, complexity, and
interference--is scored from 0 to 5 for both motor and phonic tics,
producing a tic severity score of 0 to 25 for each of Vocal Tic
Severity Score (VTSS) and Motor Tic Severity Score (MTSS). Added
together, these comprise the total tic severity (TTS) score.
Separately, impairment of the patient's life is scored on a scale
of 0 to 50, wherein 0 indicates no impairment, 10 is minimal, 20 is
mild, 30 is moderate, 40 is marked, and 50 is severe, yielding an
impairment score. When the Impairment score is added to the TTS
score, this comprises the complete Global Severity Score (GSS) of
the YGTSS.
[0536] The Tourette Syndrome Patient Global Impression of Change
(TS-PGIC) is a seven-point scale in which -3 indicates very much
worse, -2 indicates much worse, -1 indicated minimally worse, 0
indicated no change, 1 indicates minimally improved, 2 indicates
much improved, and 3 indicates very much improved.
[0537] The GTS-QOL consists of two parts. The first part is
typically a twenty-seven question assessment of various aspects of
how tics affect the subject's life, each to be rated on a
five-choice scale of no problem, slight problem, moderate problem,
marked problem, or severe problem. The second part is a simple
rating of the subject's life satisfaction, where 100 is extremely
satisfied and 0 is extremely dissatisfied.
[0538] The Tic-Free Interval is a five-point scale in which 1
indicates an interval of at least one day since the last tic, 2
indicates an interval of between 6 hours to less than one day since
the last tic, 3 indicates an interval of between one hour and less
than 6 hours since the last tic, 4 indicates an interval of between
five minutes to less than one hour since the last tic, and 5
indicates less than five minutes since the last tic.
[0539] The term "VMAT2" refers to vesicular monoamine transporter
2, an integral membrane protein that acts to transport
monoamines--particularly neurotransmitters such as dopamine,
norepinephrine, serotonin, and histamine--from cellular cytosol
into synaptic vesicles.
[0540] The term "VMAT2-mediated disorder," refers to a disorder
that is characterized by abnormal VMAT2 activity. A VMAT2-mediated
disorder may be completely or partially mediated by modulating
VMAT2. In particular, a VMAT2-mediated disorder is one in which
inhibition of VMAT2 results in some effect on the underlying
disorder e.g., administration of a VMAT2 inhibitor results in some
improvement in at least some of the patients being treated.
[0541] The term "VMAT2 inhibitor", "inhibit VMAT2", or "inhibition
of VMAT2" refers to the ability of a compound disclosed herein to
alter the function of VMAT2. A VMAT2 inhibitor may block or reduce
the activity of VMAT2 by forming a reversible or irreversible
covalent bond between the inhibitor and VMAT2 or through formation
of a noncovalently bound complex. Such inhibition may be manifest
only in particular cell types or may be contingent on a particular
biological event. The term "VMAT2 inhibitor", "inhibit VMAT2", or
"inhibition of VMAT2" also refers to altering the function of VMAT2
by decreasing the probability that a complex forms between a VMAT2
and a natural substrate
[0542] The compounds disclosed herein can exist as therapeutically
acceptable salts. The term "therapeutically acceptable salt," as
used herein, represents salts or zwitterionic forms of the
compounds disclosed herein which are therapeutically acceptable as
defined herein. The salts can be prepared during the final
isolation and purification of the compounds or separately by
reacting the appropriate compound with a suitable acid or base.
Therapeutically acceptable salts include acid and basic addition
salts.
[0543] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecyl sulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0544] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0545] While it may be possible for the compounds of the subject
invention to be administered as the raw chemical, it is also
possible to present them as a pharmaceutical composition.
Accordingly, provided herein are pharmaceutical compositions which
comprise one or more of certain compounds disclosed herein, or one
or more pharmaceutically acceptable salts, prodrugs, or solvates
thereof, together with one or more pharmaceutically acceptable
carriers thereof and optionally one or more other therapeutic
ingredients. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences. The
pharmaceutical compositions disclosed herein may be manufactured in
any manner known in the art, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes. The
pharmaceutical compositions may also be formulated as a modified
release dosage form, including delayed-, extended-, prolonged-,
sustained-, pulsatile-, controlled-, accelerated- and fast-,
targeted-, programmed-release, and gastric retention dosage forms.
These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art (.
[0546] The compositions include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal,
sublingual and intraocular) administration although the most
suitable route may depend upon for example the condition and
disorder of the recipient. The compositions may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Typically, these methods
include the step of bringing into association a compound of the
subject invention or a pharmaceutically salt, prodrug, or solvate
thereof ("active ingredient") with the carrier which constitutes
one or more accessory ingredients. In general, the compositions are
prepared by uniformly and intimately bringing into association the
active ingredient with liquid carriers or finely divided solid
carriers or both and then, if necessary, shaping the product into
the desired formulation.
[0547] Formulations of the compounds disclosed herein suitable for
oral administration may be presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granules; as a solution or
a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0548] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. The tablets may optionally be coated or
scored and may be formulated so as to provide slow or controlled
release of the active ingredient therein. All formulations for oral
administration should be in dosages suitable for such
administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, the active
compounds may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols. In
addition, stabilizers may be added. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee coatings for identification or to characterize
different combinations of active compound doses.
[0549] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, saline or sterile pyrogen-free water,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0550] Formulations for parenteral administration include aqueous
and non-aqueous (oily) sterile injection solutions of the active
compounds which may contain antioxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. Suitable lipophilic solvents or vehicles include fatty oils
such as sesame oil, or synthetic fatty acid esters, such as ethyl
oleate or triglycerides, or liposomes. Aqueous injection
suspensions may contain substances which increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers or agents which increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions.
[0551] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0552] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0553] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter, polyethylene
glycol, or other glycerides.
[0554] Certain compounds disclosed herein may be administered
topically, that is by non-systemic administration. This includes
the application of a compound disclosed herein externally to the
epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0555] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin to the site of inflammation such as gels, liniments,
lotions, creams, ointments or pastes, and drops suitable for
administration to the eye, ear or nose.
[0556] For administration by inhalation, compounds may be delivered
from an insufflator, nebulizer pressurized packs or other
convenient means of delivering an aerosol spray. Pressurized packs
may comprise a suitable propellant such as dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. Alternatively, for administration by inhalation or
insufflation, the compounds according to the invention may take the
form of a dry powder composition, for example a powder mix of the
compound and a suitable powder base such as lactose or starch. The
powder composition may be presented in unit dosage form, in for
example, capsules, cartridges, gelatin or blister packs from which
the powder may be administered with the aid of an inhalator or
insufflator.
[0557] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.
[0558] Compounds may be administered orally or via injection at a
dose of from 0.1 to 500 mg/kg per day. The dose range for adult
humans is generally from 5 mg to 2 g/day. Tablets or other forms of
presentation provided in discrete units may conveniently contain an
amount of one or more compounds which is effective at such dosage
or as a multiple of the same, for instance, units containing 5 mg
to 500 mg, usually around 10 mg to 200 mg.
[0559] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0560] In certain embodiments, the compounds disclosed herein may
be formulated or administered using any of formulations and methods
disclosed in U.S. patent application Ser. No. 14/030,322, filed
Sep. 18, 2013, which is hereby incorporated by reference in its
entirety.
[0561] The compounds can be administered in various modes, e.g.
orally, topically, or by injection. The precise amount of compound
administered to a patient will be the responsibility of the
attendant physician. The specific dose level for any particular
patient will depend upon a variety of factors including the
activity of the specific compound employed, the age, body weight,
general health, sex, diets, time of administration, route of
administration, rate of excretion, drug combination, the precise
disorder being treated, and the severity of the disorder being
treated. Also, the route of administration may vary depending on
the disorder and its severity.
[0562] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
compounds may be administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disorder.
[0563] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously or temporarily suspended for a certain length of
time (i.e., a "drug holiday").
[0564] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disorder is retained. Patients can, however, require intermittent
treatment on a long-term basis upon any recurrence of symptoms.
[0565] 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 as disclosed herein or a pharmaceutically acceptable salt,
solvate, or prodrug thereof.
[0566] VMAT2-mediated disorders, include, but are not limited to,
chronic hyperkinetic movement disorders, Huntington's disease,
hemiballismus, senile chorea, tic disorders, tardive dyskinesia,
dystonia, Tourette syndrome, depression, cancer, rheumatoid
arthritis, psychosis, multiple sclerosis, asthma, and/or any
disorder which can lessened, alleviated, or prevented by
administering a VMAT2 inhibitor.
[0567] Also disclosed herein are methods of treating abnormal
muscular activity, abnormal involuntary movement, or movement
disorders, comprising administering to a subject having or
suspected of having such a disorder, a therapeutically effective
amount of a compound as disclosed herein or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
[0568] Movement disorders include akathisia, akinesia, ataxia,
athetosis, ballismus, bradykinesia, cerebral palsy, chorea,
corticobasal degeneration, dyskinesias (e.g., paroxysmal), dystonia
(general, segmental, focal) including blepharospasm, writer's cramp
(limb dystonia), laryngeal dystonia (spasmodic dysphonia), and
oromandibular dystonia, essential tremor, geniospasm, hereditary
spastic paraplegia, Huntington's Disease, multiple system atrophy
(Shy Drager Syndrome), myoclonus, Parkinson's Disease, Parkinson's
disease levodopa-induced dyskinesia, parkinsonism, progressive
supranuclear palsy, restless legs syndrome, Rett Syndrome,
spasmodic torticollis (cervical dystonia), spasticity due to
stroke, cerebral palsy, multiple sclerosis, spinal cord or brain
injury, stereotypic movement disorder, stereotypy, Sydenham's
Chorea, synkinesis, tardive dyskinesia, tics, Tourette syndrome,
and Wilson's Disease.
[0569] In certain embodiments, a method of treating abnormal
muscular activity, abnormal involuntary movement, or movement
disorder comprises administering to the subject a therapeutically
effective amount of a compound as disclosed herein, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, so
as to affect: (1) decreased inter-individual variation in plasma
levels of the compound or a metabolite thereof; (2) increased
average plasma levels of the compound or decreased average plasma
levels of at least one metabolite of the compound per dosage unit;
(3) decreased inhibition of, and/or metabolism by at least one
cytochrome P.sub.450 or monoamine oxidase isoform in the subject;
(4) decreased metabolism via at least one polymorphically-expressed
cytochrome P.sub.450 isoform in the subject; (5) at least one
statistically-significantly improved disorder-control and/or
disorder-eradication endpoint; (6) an improved clinical effect
during the treatment of the disorder, (7) prevention of recurrence,
or delay of decline or appearance, of abnormal alimentary or
hepatic parameters as the primary clinical benefit, or (8)
reduction or elimination of deleterious changes in any diagnostic
hepatobiliary function endpoints, as compared to the corresponding
non-isotopically enriched compound.
[0570] In certain embodiments, inter-individual variation in plasma
levels of the compounds as disclosed herein, or metabolites
thereof, is decreased; average plasma levels of the compound as
disclosed herein are increased; average plasma levels of a
metabolite of the compound as disclosed herein are decreased;
inhibition of a cytochrome P.sub.450 or monoamine oxidase isoform
by a compound as disclosed herein is decreased; or metabolism of
the compound as disclosed herein by at least one
polymorphically-expressed cytochrome P.sub.450 isoform is
decreased; by greater than about 5%, greater than about 10%,
greater than about 20%, greater than about 30%, greater than about
40%, or by greater than about 50% as compared to the corresponding
non-isotopically enriched compound.
[0571] Plasma levels of the compound as disclosed herein, or
metabolites thereof, may be measured using the methods described by
Li et al. Rapid Communications in Mass Spectrometry 2005, 19,
1943-1950; Jindal, et al., Journal of Chromatography, Biomedical
Applications 1989, 493(2), 392-7; Schwartz, et al., Biochemical
Pharmacology 1966, 15(5), 645-55; Mehvar, et al., Drug Metabolism
and Disposition 1987, 15(2), 250-5; Roberts et al., Journal of
Chromatography, Biomedical Applications 1981, 226(1), 175-82; and
any references cited therein or any modifications made thereof.
[0572] Examples of cytochrome P.sub.450 isoforms in a mammalian
subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1,
CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,
CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1,
CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11,
CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1,
CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.
[0573] Examples of monoamine oxidase isoforms in a mammalian
subject include, but are not limited to, MAO.sub.A, and
MAO.sub.B.
[0574] The inhibition of the cytochrome P.sub.450 isoform is
measured by the method of Ko et al. (British Journal of Clinical
Pharmacology, 2000, 49, 343-351). The inhibition of the MAO.sub.A
isoform is measured by the method of Weyler et al. (J. Biol Chem.
1985, 260, 13199-13207). The inhibition of the MAO.sub.B isoform is
measured by the method of Uebelhack et al. (Pharmacopsychiatry,
1998, 31, 187-192).
[0575] Examples of polymorphically-expressed cytochrome P.sub.450
isoforms in a mammalian subject include, but are not limited to,
CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
[0576] The metabolic activities of liver microsomes, cytochrome
P.sub.450 isoforms, and monoamine oxidase isoforms are measured by
the methods described herein.
[0577] Examples of improved disorder-control and/or
disorder-eradication endpoints, or improved clinical effects
include, but are not limited to: [0578] b. improved Unified
Huntington's Disease Rating Scale (UHDRS) scores; [0579] c.
improved Total Maximal Chorea (TMC) Scores of the UHDRS; [0580] d.
improved Total Motor Scores (TMS) of the UHDRS; [0581] e. improved
Patient Global Impression of Change (PGIC) scores; [0582] f.
improved Clinical Global Impression of Change (CGIC) scores; [0583]
g. improved Unified Parkinson's Disease Rating Scale scores,
including the dysarthria score; [0584] h. improved Abnormal
Involuntary Movement Scale (AIMS) scores; [0585] i. improved Goetz
Dyskinesia Rating Scale scores; [0586] j. improved Unified
Dyskinesia Rating Scale scores; [0587] k. improved PDQ-39
Parkinson's Disease Questionnaire scores; [0588] l. improved Global
Primate Dyskinesia Rating Scale scores; [0589] m. improved Berg
Balance Test scores; [0590] n. improved Physical Functioning Scale
of the SF-36 scores; [0591] o. reduced Hospital Anxiety and
Depression Scale (HADS) scores; [0592] p. reduced Columbia Suicide
Severity Rating Scale (C-SSRS) scores; [0593] q. improved
Swallowing Disturbance Questionnaire (SDQ) scores; [0594] r.
improved (reduced) Barnes Akathisia Rating Scale (BARS) scores;
[0595] s. reduced Epworth Sleepiness Scale (ESS) scores; [0596] t.
improved modified Craniocervical Dystonia 24 (CDQ-24) score; [0597]
u. Montreal Cognitive Assessment (MoCA); [0598] v. improved Yale
Global Tic Severity Scale (YGTSS) scores, including Motor Tic
Severity, Vocal Tic Severity, Total Tic Severity Score (TTS)
Impairment, and Global Severity (GSS) scores thereof; [0599] w.
improved (reduced) Total Tic Severity Score (TTS); [0600] x.
improved Tourette Syndrome Clinical Global Impression (TS-CGI)
score; [0601] y. improved Patient Global Impression of Severity in
Tourette Syndrome (TS-PGIS) score; [0602] z. Children's Depression
Inventory 2 (CDI-2; Parent and Self-report versions); [0603] aa.
Children's Columbia Suicide Severity Rating Scale (C-SSRS); [0604]
bb. Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)
score; [0605] cc. Gilles de la Tourette Syndrome-Quality of Life
(GTS-QOL), including the physical/activities of daily living
subscale score, the overall life satisfaction score as measured by
the visual analog scale (VAS), the psychological subscale score,
obsessive-compulsive subscale score, and/or the cognitive subscale
score thereof;
[0606] Examples of diagnostic hepatobiliary function endpoints
include, but are not limited to, alanine aminotransferase ("ALT"),
serum glutamic-pyruvic transaminase ("SGPT"), aspartate
aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase,
alkaline phosphatase ("ALP"), ammonia levels, bilirubin,
gamma-glutamyl transpeptidase ("GGTP," ".gamma.-GTP," or "GGT"),
leucine aminopeptidase ("LAP"), liver biopsy, liver
ultrasonography, liver nuclear scan, 5'-nucleotidase, and blood
protein. Hepatobiliary endpoints are compared to the stated normal
levels as given in "Diagnostic and Laboratory Test Reference",
4.sup.th edition, Mosby, 1999. These assays are run by accredited
laboratories according to standard protocol.
[0607] Besides being useful for human treatment, certain compounds
and formulations disclosed herein may also be useful for veterinary
treatment of companion animals, exotic animals and farm animals,
including mammals, rodents, and the like. More preferred animals
include horses, dogs, and cats.
Combination Therapy
[0608] The compounds disclosed herein may also be combined or used
in combination with other agents useful in the treatment of
VMAT2-mediated disorders. Or, by way of example only, the
therapeutic effectiveness of one of the compounds described herein
may be enhanced by administration of an adjuvant (i.e., by itself
the adjuvant may only have minimal therapeutic benefit, but in
combination with another therapeutic agent, the overall therapeutic
benefit to the patient is enhanced).
[0609] Such other agents, adjuvants, or drugs, may be administered,
by a route and in an amount commonly used therefor, simultaneously
or sequentially with a compound as disclosed herein. When a
compound as disclosed herein is used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound disclosed herein may be
utilized, but is not required.
[0610] In certain embodiments, the compounds disclosed herein can
be combined with one or more dopamine precursors, including, but
not limited to, levodopa.
[0611] In certain embodiments, the compounds disclosed herein can
be combined with one or more DOPA decarboxylase inhibitors,
including, but not limited to, carbidopa.
[0612] In certain embodiments, the compounds disclosed herein can
be combined with one or more catechol-O-methyl transferase (COMT)
inhibitors, including, but not limited to, entacapone and
tolcapone.
[0613] In certain embodiments, the compounds disclosed herein can
be combined with one or more dopamine receptor agonists, including,
but not limited to, apomorphine, bromocriptine, ropinirole, and
pramipexole.
[0614] In certain embodiments, the compounds disclosed herein can
be combined with one or more neuroprotective agents, including, but
not limited to, selegeline and riluzole.
[0615] In certain embodiments, the compounds disclosed herein can
be combined with one or more NMDA antagonists, including, but not
limited to, amantidine.
[0616] In certain embodiments, the compounds disclosed herein can
be combined with one or more anti-psychotics, including, but not
limited to, chlorpromazine, levomepromazine, promazine,
acepromazine, triflupromazine, cyamemazine, chlorproethazine,
dixyrazine, fluphenazine, perphenazine, prochlorperazine,
thiopropazate, trifluoperazine, acetophenazine, thioproperazine,
butaperazine, perazine, periciazine, thioridazine, mesoridazine,
pipotiazine, haloperidol, trifluperidol, melperone, moperone,
pipamperone, bromperidol, benperidol, droperidol, fluanisone,
oxypertine, molindone, sertindole, ziprasidone, flupentixol,
clopenthixol, chlorprothixene, thiothixene, zuclopenthixol,
fluspirilene, pimozide, penfluridol, loxapine, clozapine,
olanzapine, quetiapine, tetrabenazine, sulpiride, sultopride,
tiapride, remoxipride, amisulpride, veralipride, levosulpiride,
lithium, prothipendyl, risperidone, clotiapine, mosapramine,
zotepine, pripiprazole, and paliperidone.
[0617] In certain embodiments, the compounds disclosed herein can
be combined with one or more benzodiazepines ("minor
tranquilizers"), including, but not limited to alprazolam,
adinazolam, bromazepam, camazepam, clobazam, clonazepam,
clotiazepam, cloxazolam, diazepam, ethyl loflazepate, estizolam,
fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam,
medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium
clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam,
and chlordiazepoxide.
[0618] In certain embodiments, the compounds disclosed herein can
be combined with olanzapine or pimozide.
[0619] The compounds disclosed herein can also be administered in
combination with other classes of compounds, including, but not
limited to, anti-retroviral agents; CYP3A inhibitors; CYP3A
inducers; protease inhibitors; adrenergic agonists;
anti-cholinergics; mast cell stabilizers; xanthines; leukotriene
antagonists; glucocorticoids treatments; local or general
anesthetics; non-steroidal anti-inflammatory agents (NSAIDs), such
as naproxen; antibacterial agents, such as amoxicillin; cholesteryl
ester transfer protein (CETP) inhibitors, such as anacetrapib;
anti-fungal agents, such as isoconazole; sepsis treatments, such as
drotrecogin-.alpha.; steroidals, such as hydrocortisone; local or
general anesthetics, such as ketamine; norepinephrine reuptake
inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors
(DARIs), such as methylphenidate; serotonin-norepinephrine reuptake
inhibitors (SNRIs), such as milnacipran; sedatives, such as
diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such
as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors
(SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such
as selegiline; hypothalamic phospholipids; endothelin converting
enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as
tramadol; thromboxane receptor antagonists, such as ifetroban;
potassium channel openers; thrombin inhibitors, such as hirudin;
hypothalamic phospholipids; growth factor inhibitors, such as
modulators of PDGF activity; platelet activating factor (PAF)
antagonists; anti-platelet agents, such as GPIIb/IIIa blockers
(e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists
(e.g., clopidogrel, ticlopidine and CS-747), and aspirin;
anticoagulants, such as warfarin; low molecular weight heparins,
such as enoxaparin; Factor VIIa Inhibitors and Factor Xa
Inhibitors; renin inhibitors; neutral endopeptidase (NEP)
inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors),
such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors,
such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104
(a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522
(also known as rosuvastatin, or atavastatin or visastatin);
squalene synthetase inhibitors; fibrates; bile acid sequestrants,
such as questran; niacin; anti-atherosclerotic agents, such as ACAT
inhibitors; MTP Inhibitors; calcium channel blockers, such as
amlodipine besylate; potassium channel activators; alpha-muscarinic
agents; beta-muscarinic agents, such as carvedilol and metoprolol;
antiarrhythmic agents; diuretics, such as chlorothlazide,
hydrochiorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichioromethiazide,
polythiazide, benzothlazide, ethacrynic acid, tricrynafen,
chlorthalidone, furosenilde, musolimine, bumetanide, triamterene,
amiloride, and spironolactone; thrombolytic agents, such as tissue
plasminogen activator (tPA), recombinant tPA, streptokinase,
urokinase, prourokinase, and anisoylated plasminogen streptokinase
activator complex (APSAC); anti-diabetic agents, such as biguanides
(e.g. metformin), glucosidase inhibitors (e.g., acarbose),
insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g.,
glimepiride, glyburide, and glipizide), thiozolidinediones (e.g.
troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma
agonists; mineralocorticoid receptor antagonists, such as
spironolactone and eplerenone; growth hormone secretagogues; aP2
inhibitors; phosphodiesterase inhibitors, such as PDE III
inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g.,
sildenafil, tadalafil, vardenafil); protein tyrosine kinase
inhibitors; antiinflammatories; antiproliferatives, such as
methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil;
chemotherapeutic agents; immunosuppressants; anticancer agents and
cytotoxic agents (e.g., alkylating agents, such as nitrogen
mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and
triazenes); antimetabolites, such as folate antagonists, purine
analogues, and pyrridine analogues; antibiotics, such as
anthracyclines, bleomycins, mitomycin, dactinomycin, and
plicamycin; enzymes, such as L-asparaginase; farnesyl-protein
transferase inhibitors; hormonal agents, such as glucocorticoids
(e.g., cortisone), estrogens/antiestrogens,
androgens/antiandrogens, progestins, and luteinizing
hormone-releasing hormone anatagonists, and octreotide acetate;
microtubule-disruptor agents, such as ecteinascidins;
microtubule-stablizing agents, such as pacitaxel, docetaxel, and
epothilones A-F; plant-derived products, such as vinca alkaloids,
epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;
prenyl-protein transferase inhibitors; and cyclosporins; steroids,
such as prednisone and dexamethasone; cytotoxic drugs, such as
azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as
tenidap; anti-TNF antibodies or soluble TNF receptor, such as
etanercept, rapamycin, and leflunimide; and cyclooxygenase-2
(COX-2) inhibitors, such as celecoxib and rofecoxib; and
miscellaneous agents such as, hydroxyurea, procarbazine, mitotane,
hexamethylmelamine, gold compounds, platinum coordination
complexes, such as cisplatin, satraplatin, and carboplatin.
[0620] Thus, in another aspect, certain embodiments provide methods
for treating VMAT2-mediated disorders in a subject in need of such
treatment comprising administering to said subject an amount of a
compound disclosed herein effective to reduce or prevent said
disorder in the subject, in combination with at least one
additional agent for the treatment of said disorder. In a related
aspect, certain embodiments provide therapeutic compositions
comprising at least one compound disclosed herein in combination
with one or more additional agents for the treatment of
VMAT2-mediated disorders.
General Synthetic Methods for Preparing Compounds
[0621] The compounds as disclosed herein can be prepared by methods
known to one of skill in the art and routine modifications thereof,
and/or following procedures similar to those described in US
20100130480 (paragraphs [0093]-[0121]), US 20120003330 (paragraphs
[0104]-[0162]), WO 2005077946; WO 2008/058261; EP 1716145; Lee et
al., J. Med. Chem., 1996, (39), 191-196; Kilbourn et al.,
Chirality, 1997, (9), 59-62; Boldt et al., Synth. Commun., 2009,
(39), 3574-3585; Rishel et al., J. Org. 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; U.S. Pat. No.
2,830,993; U.S. Pat. No. 3,045,021; WO 2007130365; WO 2008058261,
which are hereby incorporated in their entirety, and references
cited therein and routine modifications thereof.
[0622] Isotopic hydrogen can be introduced into a compound as
disclosed herein by synthetic techniques that employ deuterated
reagents, whereby incorporation rates are pre-determined; and/or by
exchange techniques, wherein incorporation rates are determined by
equilibrium conditions, and may be highly variable depending on the
reaction conditions. Synthetic techniques, where tritium or
deuterium is directly and specifically inserted by tritiated or
deuterated reagents of known isotopic content, may yield high
tritium or deuterium abundance, but can be limited by the chemistry
required. Exchange techniques, on the other hand, may yield lower
tritium or deuterium incorporation, often with the isotope being
distributed over many sites on the molecule.
[0623] In certain embodiments, specific examples of compounds of
the present invention include a compound selected from the list
described in paragraph [0122] of US 20100130480 and paragraph
[0163] of US 20120003330, which are hereby incorporated by
reference.
[0624] Changes in the in vitro metabolic properties of certain of
the compounds disclosed herein as compared to their
non-isotopically enriched analogs and methods of determining such
changes have been described in paragraph [0125] of US 20100130480
and paragraphs [0165]-[0185] of US 20120003330, which are hereby
incorporated by reference.
Formulations
[0625] Compounds may be formulated for use in the dosage regimens
and methods disclosed herein by methods known in the art, e.g., as
disclosed in US2014/0336386. Examples of these formulations are
provided below.
[0626] 15 mg d.sub.6-Tetrabenazine Gastro-Erosional Extended
Release (Small Tablet) (Formulation A).
[0627] Table 1 below discloses the elements of a 350 mg total
weight gastro-erosional granulation formulation tablet comprising
15 mg (RR,
SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methylpropyl)-2-
H-benzo[a]quinolizin-2-one.
TABLE-US-00001 TABLE 1 Material mg/tab % d.sub.6-Tetrabenazine
(milled) 15.0 4.3 Mannitol Powder 185.4 53.0 Microcrystalline
Cellulose 61.8 17.7 PVP K29/32 14.0 4.0 Tween 80 (Polysorbate 80)
3.8 1.1 Mannogem .RTM. EZ (spray dried mannitol) 31.5 9.0 POLYOX
.RTM. N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals: 350.0
100.0
[0628] d.sub.6-Tetrabenazine (milled) is combined along with
Mannitol Powder, Microcrystalline Cellulose, PVP K29/32 and Tween
80 (Polysorbate 80) into a high shear granulator and initially dry
mixed at high impeller and chopper speed for 5 minutes. While
mixing at high impeller speed and low chopper speed, Purified Water
is added to the mixing powders to granulate the material.
Additional mixing and water addition with high impeller and high
chopper speed continues until the desired granulation end-point is
achieved. The resulting granulation is wet screened to break up any
oversized agglomerates and the material is added to a fluid bed
drier and dried at 60.degree. C. until the desired L.O.D. (loss on
drying) is achieved. The dried material is sieved through a #20
mesh screen and the oversized material is milled to a particle size
of just under 20 mesh in size. The dried and sized material is
combined with Spray Dried Mannitol and POLYOX.RTM. N60K into a
diffusive mixer (V-Blender) where it is blended for 15 minutes.
Magnesium Stearate is then passed through a #30 mesh screen and
added to the blended material in the V-Blender. The contents are
then lubricated for 3 minutes and discharged for tablet
compression. Using a rotary tablet press fitted with punches and
dies of the desired shape and size, the lubricated blend is
compressed into tablets of a theoretical weight of 350 mg.
[0629] 7.5 mg d.sub.6-Tetrabenazine Gastro-Erosional Extended
Release (Small Tablet) (Formulation A).
[0630] Table 2 below discloses the elements of a 350 mg total
weight gastro-erosional granulation formulation tablet comprising
7.5 mg d.sub.6-tetrabenazine. Same process as described for Example
1.
TABLE-US-00002 TABLE 2 Material mg/tab % d.sub.6-Tetrabenazine
(milled) 7.5 2.1 Mannitol Powder 191.0 54.6 Microcrystalline
Cellulose 63.7 18.2 PVP K29/32 14.0 4.0 Tween 80 (Polysorbate 80)
3.8 1.1 Mannogem EZ (spray dried mannitol) 31.5 9.0 POLYOX .RTM.
N60K 35.0 10.0 Magnesium Stearate 3.5 1.0 Totals: 350.0 100.0
[0631] 15 mg d.sub.6-Tetrabenazine Gastro-Retentive Extended
Release (Large Tablet) (Formulation B).
[0632] Table 3 below discloses the elements of a 700 mg total
weight gastro-retentive formulation tablet comprising 15 mg
d.sub.6-tetrabenazine. The gastro-retentive tablet is an elongated
capsule having dimensions of approximately 0.7087 in. long by
0.3071 in. wide, having rounded ends with a cup depth of 0.0540 in.
on each opposing side.
TABLE-US-00003 TABLE 3 Material mg/tab % d.sub.6-Tetrabenazine
(milled) 15.0 2.1 Mannitol Powder 357.5 51.1 Microcrystalline
Cellulose 119.0 17.0 PVP K29/32 26.0 3.7 Tween 80 (Polysorbate 80)
7.5 1.1 Mannogem EZ (spray dried mannitol) 45.5 6.5 POLYOX .RTM.
N60K 122.5 17.5 Magnesium Stearate 7.0 1.0 Totals: 700.0 100.0
[0633] 7.5 mg d.sub.6-Tetrabenazine Gastro-Retentive Extended
Release (Large Tablet) (Formulation B).
[0634] Table 4 below discloses the elements of a 700 mg total
weight gastro-retentive formulation tablet comprising 7.5 mg
d.sub.6-tetrabenazine. The gastro-retentive tablet is an elongated
capsule having dimensions of approximately 0.7087 in. long by
0.3071 in. wide, having rounded ends with a cup depth of 0.0540 in.
on each opposing side. Same process as described for Example 1. But
theoretical compression weight is 700 mg.
TABLE-US-00004 TABLE 4 Material mg/tab % d.sub.6-Tetrabenazine
(milled) 7.5 1.1 Mannitol Powder 363.0 51.9 Microcrystalline
Cellulose 121.0 17.3 PVP K29/32 26.0 3.7 Tween 80 (Polysorbate 80)
7.5 1.1 Mannogem .RTM. EZ (spray dried mannitol) 45.5 6.5 POLYOX
.RTM. N60K 122.5 17.5 Magnesium Stearate 7.0 1.0 Totals: 700.0
100.0
[0635] 6 mg d.sub.6-Tetrabenazine Immediate Release Tablet.
[0636] Table 5 below discloses the elements of a 125 mg total
weight immediate-release tablet comprising 6 mg
d.sub.6-tetrabenazine.
TABLE-US-00005 TABLE 5 Material mg/tab % d.sub.6-Tetrabenazine
(milled) 6.0 4.8 Mannitol Powder 75.0 60.0 Microcrystalline
Cellulose 25.0 20.0 Sodium Starch Glycolate 2.5 2.0 PVP K29/32 6.0
4.8 Tween 80 (Polysorbate 80) 1.0 0.8 Mannogem .RTM. EZ (spray
dried mannitol) 5.8 4.6 Sodium Starch Glycolate 2.5 2.0 Magnesium
Stearate 1.2 1.0 Totals: 125.0 100.0
[0637] d.sub.6-Tetrabenazine (milled) is combined along with
Mannitol Powder, Microcrystalline Cellulose, Sodium Starch
Glycolate, PVP K29/32 and Tween 80 (Polysorbate 80) into a high
shear granulator and initially dry mixed at high impeller and
chopper speed for 5 minutes. While mixing at high impeller speed
and low chopper speed, Purified Water is added to the mixing
powders to granulate the material. Additional mixing and water
addition with high impeller and high chopper speed continues until
the desired granulation end-point is achieved. The resulting
granulation is wet screened to break up any oversized agglomerates
and the material is added to a fluid bed drier and dried at
60.degree. C. until the desired L.O.D. (loss on drying) is
achieved. The dried material is sieved through a #20 mesh screen
and the oversized material is milled to a particle size of just
under 20 mesh in size. The dried and sized material is combined
with Spray Dried Mannitol and Sodium Starch Glycolate.
[0638] In all of the the methods and compositions disclosed herein
using deutetrabenazine, the deutetrabenazine may be administered or
formulated as part of a pharmaceutical composition as disclosed in
tables 1-5 above.
Clinical Trials and Results
First-HD
[0639] First-HD was a randomized, double-blind, placebo-controlled,
parallel-group study designed to evaluate the efficacy, safety, and
tolerability of deutetrabenazine in subjects with chorea associated
with HD. This trial was conducted in the United States and Canada,
in collaboration with the Huntington Study Group.
Study Design
[0640] Subjects in First-HD were treated with deutetrabenazine or
placebo, starting at 6 mg once per day and titrating weekly to
doses of up to 24 mg twice per day (48 mg total maximum daily
dose). A total of 90 subjects (45 in each group) were enrolled for
evaluation over 13 weeks. Subjects were individually titrated to an
optimal dose over up to eight weeks, received maintenance therapy
at the optimal dose for four weeks, and were taken off study
medication in the final week of the trial.
Subject Disposition and Demographic and Baseline
Characteristics
[0641] Of the 90 subjects randomized, 87 subjects completed the
study. The study population was typical for subjects with chorea
associated with HD. At baseline, the mean age of the subjects was
53.7 years. The majority of subjects were white (92.2%) and male
(55.6%). The mean CAG repeat length among the subject population
was 43.9. At baseline, the mean TMC score was 12.7 in the overall
population (range 8.0-19.5).
Study Endpoints and Measurements
[0642] The primary efficacy endpoint for the study was the change
from baseline to maintenance therapy (average of Week 9 and Week 12
values) in the maximal chorea score of the UHDRS. The total maximal
score, or TMC, is a clinician-based, quantitative assessment of
chorea in seven body regions: face, mouth/tongue, trunk, and the
four extremities, with higher scores representing more severe
chorea. This is the same endpoint that was accepted by the FDA when
it considered and approved tetrabenazine in 2008 (NDA 21894).
[0643] The total motor score (TMS) of the UHDRS was prespecified as
an additional efficacy endpoint in First-HD. The TMS assesses all
the motor features of HD, including items addressing characteristic
motor abnormalities other than chorea, such as dystonia, gait,
parkinsonism, and postural instability.
[0644] The clinical relevance of the change in the TMC score was
assessed with four prespecified secondary endpoints that assessed
changes from baseline to end of treatment (Week 12). These
secondary endpoints were tested in a hierarchical manner:
[0645] 1. Treatment success based on patient global impression of
change (PGIC);
[0646] 2. Treatment success based on clinical global impression of
change (CGIC);
[0647] 3. Physical Functioning Scale of the SF-36; and
[0648] 4. Balance, as assessed by the Berg Balance Test (BBT).
[0649] The PGIC and CGIC are single-item questionnaires that ask
the subject and investigator, respectively, to assess a subject's
overall HD symptoms at specific visits after initiating therapy.
Both assessments use a 7-point Likert Scale, with responses ranging
from Very Much Worse (-3) to Very Much Improved (+3) to assess
overall response to therapy. Patients and clinicians were asked,
"With respect to your (or the subject's) overall Huntington's
disease symptoms, how would you describe yourself (or the subject)
compared to immediately before starting study medication."
Treatment success according to these scales was defined as a rating
of Much Improved or Very Much Improved at Week 12. Subjects who did
not have a response at Week 12 were assumed to be treatment
failures.
[0650] Adverse events (AE) and their potential association with
treatment were also monitored. Categories of AEs of particular
focus included those known to be associated with tetrabenazine use:
[0651] Psychiatric disorders: insomnia, depression/agitated
depression, abnormal dreams, agitation, anxiety, suicidal ideation,
compulsions, impulsive behavior, and sleep disorders; [0652]
Nervous system disorders: somnolence, dizziness,
akathisia/restlessness, cognitive disorders, drooling, dyskinesia,
migraine, headache, loss of consciousness, and syncope (fainting);
[0653] General disorders: irritability, fatigue, gait disturbance,
chest pain, and hangover; and [0654] Gastrointestinal disorders:
diarrhea, dry mouth, constipation, nausea, upper abdominal pain,
dyspepsia, frequent bowel movements, gastrointestinal pain,
vomiting, dysphagia, flatulence, and salivary hypersecretion.
[0655] In addition to AE reporting, rating scales were used to
monitor for potential subclinical toxicity due to excessive
monoamine depletion. Such safety scales were employed in the
tetrabenazine development program. These scales applied in First-HD
included the Hospital Anxiety and Depression Scale (HADS), the
Columbia Suicide Severity Rating Scale (C-SSRS), the Swallowing
Disturbance Questionnaire (SDQ), the Unified Parkinson's Disease
Rating Scale (dysarthria item) (UPDRS [dysarthria]), the Barnes
Akathisia Rating Scale (BARS), and the Epworth Sleepiness Scale
(ESS). In addition, the UHDRS, which includes cognitive,
behavioral, and functional measures, was performed at key
visits.
[0656] The Swallowing Disturbance 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
assessment has been validated in patients with Parkinson's disease
and has been shown to be a sensitive and accurate tool for
identifying patients with swallowing disturbances arising from
different etiologies. The SDQ is recommended by the National
Institute of Neurological Disorders and Stroke Common data elements
for assessing swallowing impairment in Parkinson's disease, and
thus is also relevant for patients with HD, given they may have
bradykinesia and other parkinsonian symptoms as part of their
illness.
[0657] Minor fluctuations in vital signs (blood pressure, heart
rate, respiratory rate, and temperature) were observed during the
study.
Results
[0658] The mean dose at the end of treatment period was 39.7 mg (SD
9.3 mg, range 12-48 mg) in the deutetrabenazine group and 43. 3 mg
(7.6 mg, range 12-48 mg) in the placebo group. Mean dosage for the
10 deutetrabenazine group subjects with impaired CYP2D6 function
(poor metabolizers or on strong CYP2D6 inhibiting medications) was
34.8 mg (3.8 mg, range 30-42 mg). The overall compliance rates were
94.1% and 95.1% for placebo and deutetrabenazine groups,
respectively.
[0659] Treatment with deutetrabenazine resulted in improvements in
all endpoints and reduced incidence of adverse events. In the
results below, DTBZ=deutetrabenazine, CI=confidence interval (based
on the t-distribution); SD=standard deviation; Least squares means
and p-value were obtained from a two-sided test of the effect of
treatment from and analysis of covariance model with a term for
treatment and the baseline score as covariate.
[0660] Total Maximal Chorea Score (TMC).
[0661] Treatment with deutetrabenazine resulted in robust
improvement in maximal chorea score. TMC score at a given time
point is determined from Item 12 of the UHDRS. Change in TMC is the
difference between baseline and maintenance therapy values. The
baseline value is the mean of the Screening and Day 0 values and
the maintenance therapy value is the mean of the Week 9 and Week 12
values. For the primary endpoint, subjects receiving
deutetrabenazine achieved a significant reduction of 2.5 units on
the TMC score from baseline to maintenance therapy compared with
placebo (p<0.0001). This reduction in maximal chorea represented
a reduction of 21 percentage points compared with placebo
(p<0.0001). Deutetrabenazine (DTBZ) was administered at
approximately half the daily dose of tetrabenazine. The efficacy of
deutetrabenazine was therefore achieved at about half the daily
dose of tetrabenazine.
TABLE-US-00006 TABLE 6 Total Maximal Chorea Score - Change from
Baseline to Maintenance Therapy Change in Total Maximal Difference
in Means Chorea Score (DTBZ - Placebo DTBZ Placebo and 95%
Statistic (N = 45) (N = 45) CI) Absolute Change in Total Maximal
Chorea Score (Primary Efficacy Endpoint) Least Squares Mean -4.4
(3.0) -1.9 (2.7) -2.5 (-3.7, -1.3) (SD) p-value -- -- <0.0001
Percentage Change in Total Maximal Chorea Score (Additional
Efficacy Endpoint) (%) Least Squares Mean -37 (25.7) -16 (19.6) -21
(-30.5, -11.1) (SD) p-value -- -- <0.0001
[0662] Total Motor Score (TMS).
[0663] Additionally, a statistically significant improvement in the
TMS of 4.0 units, compared with placebo, was observed. The fact
that the TMS improvement was greater in magnitude than the TMC
score improvement (-2.5 units), suggests a benefit of
deutetrabenazine treatment on other motor symptoms of HD, in
addition to the reduction in chorea. The majority of this
improvement was due to chorea, but the total maximal dystonia score
also contributed, with deutetrabenazine improving by 0.9 (SE 0.24)
points versus placebo 0.1 (SE 0.32) points (p=0.02). From baseline
to maintenance therapy, TMC improved by 37% in the deutetrabenazine
groups vs. 16% improvement in the placebo group (p<0.0001).
Changes in other UHDRS motor components did not differ
significantly between treatment groups, including no significant
difference in the changes in the parkinsonism subscore (finger
taps; pronation/supination; rigidity; bradykinesia; gait; tandem
walking; and retropulsion pull test scores) between
deutetrabenazine and placebo groups.
TABLE-US-00007 TABLE 7 Total Motor Score - Change from Baseline to
Maintenance Therapy Difference in Means DTBZ Placebo (DTBZ -
Placebo) and Statistic (N = 45) (N = 45) 95% CI Least Squares Mean
-7.4 (6.3) -3.4 (5.5) -4.0 (-6.5, -1.5) (SD) p-value -- --
0.0023
[0664] Total Motor Score: Comparison to Tetrabenazine.
[0665] In contrast, in a 12-week placebo-controlled study,
tetrabenazine was demonstrated to improve the TMC score of the
UHDRS but the tetrabenazine treatment failed to show statistically
significant improvement in TMS (Huntington Study Group, 2006).
These results suggest that tetrabenazine controls chorea associated
with HD, but patients may experience a possible decline in motor
function that offsets the observed benefit on chorea.
[0666] Conclusion.
[0667] Therefore, deutetrabenazine may represent a superior choice
for treatment of movement disorders generally. It is noteworthy
that deutetrabenazine achieved efficacy at about half the daily
dose of tetrabenazine.
[0668] Patient Global Impression of Change (PGIC) and Clinical
Global Impression of Change (CGIC).
[0669] At end of therapy, 51% (23 of 45) of
deutetrabenazine-treated subjects were much improved or very much
improved based on the PGIC, compared with 20% (9 of 45) subjects in
the placebo group (p=0.0020). Similar findings were observed by the
treating physicians, where 42% (19 of 45) deutetrabenazine-treated
subjects were assessed as having achieved treatment success based
on the CGIC compared with 13% (6 of 45) subjects in the placebo
group (p=0.0022). These results indicate that
deutetrabenazine-treated subjects experienced a clinically
meaningful benefit on their overall symptoms of HD and their
treating clinicians were also able to observe the benefit.
[0670] Improvement in these physician and patient assessment scores
indicate that the improvement measured by the TMC and TMS
translated into improvement of HD symptoms and further supports the
clinical benefit of deutetrabenazine.
TABLE-US-00008 TABLE 8 Treatment Success at End of Therapy
Determined by PGIC and CGIC Difference in Percentages for DTBZ
Placebo Treatment Success (N = 45) (N = 45) (DTBZ - Placebo) and
95% CI (%) (%) (%) Patient Global Impression of Change: Treatment
Success at the End of Therapy.sup.b 51 20 31 (12.4, 49.8)
p-value.sup.c -- -- 0 0020 Clinical Global Impression of Change:
Treatment Success at the End of Therapy.sup.b 42 13 29 (11.4, 46.4)
p-value.sup.c -- -- 0.0022
[0671] SF-36 Physical Functioning Score.
[0672] The Physical Functioning Score of the SF-36 was selected as
a key secondary endpoint because it is a patient-reported
instrument that has been used in many disease states and it
assesses physical activities relevant to patients living with HD.
The 10-item physical functioning score queries patients regarding
self-care such as bathing, dressing, lifting or carrying groceries,
climbing one or more flights of stairs, bending, kneeling, walking
100 yards or more, and moderate to vigorous activities. The SF-36
physical functioning score has been shown to measure impairment
experienced by people living with HD.
[0673] The mean change from baseline to Week 12 in the SF-36
physical functioning score is provided below, where
deutetrabenazine treated subjects demonstrated a mean improvement
of 0.74 in treated patients over baseline, compared to a worsening
of 3.61 units in the placebo group (a difference of 4.3 units). In
subjects with more severe chorea at baseline (TMC>the median of
the population, or TMC>12; n=49), the benefit of
deutetrabenazine on physical functioning was more pronounced, with
a mean improvement of 7.1 units over placebo (p=0.0075).
[0674] Change from Baseline to Week 12 on the SF-36 physical
functioning score showed that SD-809-treated subjects had greater
improvement in physical function compared with placebo-treated
subjects (p=0.03). Analysis of SF-36 by baseline severity of chorea
indicated that SD-809 had a greater benefit in subjects with more
severe chorea (p=0.0075). Given the potential for chorea to
interfere with basic motor skills, gait, and walking it is not
unexpected that subjects with more impaired function would
experience greater benefit on this measure.
[0675] Given the significant negative impact that chorea has on the
patient's quality of life and physical functioning, the
statistically significant improvement in the subjects' assessment
of their ability to perform activities of daily living further
supports the clinical benefit of deutetrabenazine.
TABLE-US-00009 TABLE 9 SF-36 Physical Functioning Score - Change
from Baseline to Week 12 Change in SF-36 Score from Baseline to
Week 12 Difference in Means DTBZ Placebo (DTBZ - Placebo) Statistic
(N = 45) (N = 45) and 95% CI N 45 43 Least Squares Mean 0.74
(9.773) -3.61 (9.669) 4.34 (0.41, 8.27) (SD) p-value -- --
0.0308
[0676] Berg Balance Test.
[0677] The BBT is a 14-item assessment of balance that was used to
evaluate if reducing chorea had an impact on balance, since many
medications currently used to treat chorea may worsen balance. The
BBT was assessed as a safety measure and efficacy endpoint. As
summarized below, deutetrabenazine did not worsen balance at 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 the
BBT observed during the course of the study.
TABLE-US-00010 TABLE 10 Change in Berg Balance Test Score from
Baseline to Week 12 Change in BBT Score from Baseline to Week 12
Difference in Means DTBZ Placebo (DTBZ - Placebo) Statistic (N =
45) (N = 45) and 95% CI Least Squares 2.2 (3.47) 1.3 (4.04) 1.0
(-0.3, 2.3) Mean (SD) p-value -- -- 0.1415
[0678] Adverse Events.
[0679] Deutetrabenazine was generally well tolerated. The overall
rates of adverse events (AEs) were the same between the
deutetrabenazine and placebo groups, with (60.0%) of subjects in
each group experiencing at least one AE. There were no deaths in
the study. There was one subject with two serious AEs
(cholecystitis and agitated 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 the serious AEs in the deutetrabenazine
group also reported suicidal ideation, which was not considered a
serious AE, and subsequently withdrew from the study due to an AE
of agitation. In the placebo group, one subject reported suicidal
ideation on the Columbia Suicide Severity Rating Scale and one
subject withdrew from the study due to an AE of atrial
fibrillation. Evidence of good tolerability is further indicated by
the same rates of AEs leading to dose reduction, dose suspension
and withdrawal. Finally, CYP2D6 genetic status did not impact
dosing in this study or the rate of AE. As expected, poor
metabolizers, either through genetics or concomitant medications,
were dosed slightly lower and without additional AEs, supporting
the notion that deutetrabenazine dosing may be managed clinically
without reliance on expensive genotyping.
TABLE-US-00011 TABLE 11 Overview of Treatment-Emergent Adverse
Events DTBZ Placebo (N = 45) (N = 45) Type of Event n (%) n (%) Any
Treatment-Emergent AEs (TEAEs) 27 (60.0) 27 (60.0) Any Psychiatric
Disorders TEAE 8 (17.8) 8 (17.8) Any Nervous System Disorders TEAE
8 (17.8) 10 (22.2) Any Serious TEAEs 1 (2.2) 1 (2.2) Any TEAEs
Resulting in Dose Reduction 3 (6.7) 3 (6.7) Any TEAEs Resulting in
Dose Suspension 1 (2.2) 1 (2.2) Any TEAE that led to Withdrawal
from the Study 1 (2.2) 1 (2.2)
[0680] Similar rates of AEs were also observed among the
psychiatric and nervous system body systems, which are areas of
particular importance for patients with HD. The numbers of subjects
reporting AEs in certain system organ classes of psychiatric,
nervous system, gastrointestinal and other general disorders are
listed in Table 12 below. These body systems are highlighted
because they include many of the underlying symptoms observed in
patients with HD and were also frequent AEs observed with
tetrabenazine. Deutetrabenazine-treated subjects had low rates of
insomnia, depression, anxiety, agitation, suicidal ideation,
akathisia, irritability, and fatigue and these rates were similar
to or lower than the incidence observed in placebo-treated
subjects. Importantly, no AEs of parkinsonism or dysphagia were
reported in the deutetrabenazine group. The most common AE observed
in the deutetrabenazine group was somnolence, which was observed in
11.1% of subjects versus 4.4% in the placebo group, or a
drug-placebo difference of 6.7%.
TABLE-US-00012 TABLE 12 Treatment-Emergent Adverse Events DTBZ
Placebo (N = 45) (N = 45) System Organ Class Preferred Term n (%) n
(%) PSYCHIATRIC Insomnia 3 (6.7) 2 (4.4) DISORDERS
Depression/Agitated 2 (4.4) 3 (6.7) Depression Abnormal Dreams 1
(2.2) 1 (2.2) Agitation 1 (2.2) 0 Anxiety 1 (2.2) 1 (2.2) Suicidal
Ideation 1 (2.2) 0 Compulsions 0 1 (2.2) Impulsive Behavior 0 1
(2.2) Sleep Disorder 0 3 (6.7) NERVOUS Somnolence 5 (11.1) 2 (4.4)
SYSTEM Dizziness 2 (4.4) 4 (8.9) DISORDERS Akathisia/Restlessness 1
(2.2) 1 (2.2) Cognitive Disorder 1 (2.2) 0 Drooling 1 (2.2) 0
Dyskinesia 1 (2.2) 0 Migraine 1 (2.2) 0 Headache 0 3 (6.7) Loss of
Consciousness 0 1 (2.2) Syncope 0 1 (2.2) GENERAL Irritability 3
(6.7) 6 (13.3) DISORDERS Fatigue 3 (6.7) 2 (4.4) Gait disturbance 1
(2.2) 0 Chest pain 1 (2.2) 0 Hangover 1 (2.2) 0 GASTRO- Diarrhea 4
(8.9) 0 INTESTINAL Dry mouth 4 (8.9) 3 (6.7) DISORDERS Constipation
2 (4.4) 1 (2.2) Nausea 1 (2.2) 2 (4.4) Abdominal pain upper 1 (2.2)
0 Dyspepsia 1 (2.2) 0 Frequent bowel 1 (2.2) 0 movements
Gastrointestinal pain 1 (2.2) 0 Vomiting 0 3 (6.7) Dysphagia 0 1
(2.2) Flatulence 0 1 (2.2) Salivary hypersecretion 0 1 (2.2)
[0681] Safety.
[0682] In addition to AE reporting, rating scales were used to
monitor for potential subclinical toxicity due to excessive
monoamine depletion. Such safety scales were employed in the
tetrabenazine development program. These scales applied in First-HD
included the Hospital Anxiety and Depression Scale (HADS), the
Columbia Suicide Severity Rating Scale (C-SSRS), the Swallowing
Disturbance Questionnaire (SDQ), the Unified Parkinson's Disease
Rating Scale (dysarthria item) (UPDRS [dysarthria]), the Barnes
Akathisia Rating Scale (BARS), and the Epworth Sleepiness Scale
(ESS). In addition, the UHDRS, which includes cognitive,
behavioral, and functional measures, was performed at key
visits.
[0683] These safety scales showed that deutetrabenazine did not
cause depression, anxiety, suicidality, akathisia, somnolence, or
difficulty speaking, as between group difference on the scales were
small and not clinically significant. In fact, swallowing function,
which is an important cause of morbidity and mortality in patients
with HD, was shown to significantly improve in
deutetrabenazine-treated subjects compared with placebo and was
consistent with improvement seen in motor function. The clinical
relevance of this improvement is described below.
[0684] Swallowing Disturbance.
[0685] The Swallowing Disturbance 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
assessment has been validated in patients with Parkinson's disease
and has been shown to be a sensitive and accurate tool for
identifying patients with swallowing disturbances arising from
different etiologies. The SDQ is recommended by the National
Institute of Neurological Disorders and Stroke Common data elements
for assessing swallowing impairment in Parkinson's disease, and
thus is also relevant for patients with HD, given they may have
bradykinesia and other parkinsonian symptoms as part of their
illness. FIG. 2 presents the mean change from baseline in the SDQ
by over time, demonstrating a significant improvement in swallowing
with deutetrabenazine treatment, compared with placebo.
[0686] Additional UHDRS Assessments.
[0687] The UHDRS rating scale was assessed throughout the First-HD
Study to monitor for safety. Evaluation of the parkinsonism
subscore of the UHDRS Motor Assessment (Part I) did not identify
evidence of parkinsonism in subjects treated with deutetrabenazine
or placebo, consistent with the absence of extrapyramidal symptom
AEs. These results were further supported by the lack of meaningful
changes in either treatment group on the UPDRS dysarthria
question.
[0688] The results of the UHDRS Cognitive Assessment (Part II) also
demonstrated no meaningful changes from baseline or consistent
trends between treatment groups, indicative of no decline in
cognitive function with treatment.
[0689] The UHDRS Behavioral Assessment (Part III) demonstrated
improvement in the in the mean total behavior score for
deutetrabenazine-treated subjects compared with the placebo group,
however the difference did not achieve statistical significance.
Importantly, there was no worsening of depressed mood, apathy,
self-esteem, irritability, aggressive behavior, suicidal thoughts,
hallucinations, or delusions. The improvement in the overall score
was driven by differences in anxiety and compulsive behavior (FIG.
4 A-C).
[0690] The UHDRS Functional Assessment Score (Part IV),
Independence Scale Score (Part V) and the Total Functional Capacity
Score (Part VI), which were assessed at Baseline and again at Week
12, did not show clinically relevant changes from baseline in
either treatment group or differences between the treatment
groups.
[0691] Minor fluctuations in vital signs (blood pressure, heart
rate, respiratory rate, and temperature) were observed during the
study; these changes were generally similar in the deutetrabenazine
and placebo treatment groups and were not assessed as clinically
significant. No consistent between group differences were observed.
In addition, there was no evidence that hypotension, dizziness, or
orthostasis was associated with deutetrabenazine treatment.
[0692] Body Weight.
[0693] Compared with the placebo group, deutetrabenazine treatment
led to a mean weight gain of approximately 2.1 kg over placebo (at
week 12, mean (SD) change in body weight of +1.8 (3.4) kg for
deutetrabenazine vs -0.30 (2.5) kg in placebo (treatment effect,
+2.1 kg). Weight gain correlates with improved treatment outcome
and health in chorea patients, and may result in part from reduced
chorea (whereby the improved swallowing may lead to better intake
of food, which when combined with less caloric energy used due to
reduced abnormal involuntary movements, may translate into weight
gain), in addition to improved function or behavioral symptoms such
as anxiety, which may suppress appetite.
[0694] Adverse Events and Safety:
[0695] comparison to tetrabenazine. The variable pharmacokinetics
of tetrabenazine can affect its tolerability and limit its clinical
use. The half-lives of the circulating active metabolites, .alpha.-
and .beta.-dihydrotetrabenazine, are short. These short half-lives
necessitate frequent dosing and result in large fluctuations in
plasma concentrations. The high peak concentrations and variability
in plasma levels associated with tetrabenazine may contribute to
the poor tolerability that is often observed.
[0696] Accordingly, the prescribing information for tetrabenazine
contains several warnings regarding adverse effects and the
potential for safety issues: [0697] A boxed warning indicates that
tetrabenazine increases the risk of depression and suicidal
thoughts and behavior (suicidality) in patients with HD. [0698]
High rates of treatment-emergent adverse events were observed in
patients treated with tetrabenazine compared with placebo-treated
patients, including somnolence/sedation, insomnia, depression,
akathisia, anxiety, and fatigue (see Table # below). [0699] Dose
escalation was discontinued or dosage of study drug was reduced due
to adverse events in 52% (28 of 54) of patients randomized to
tetrabenazine. [0700] In the 12-week, randomized controlled trial
of tetrabenazine, adverse events suggestive of parkinsonism (e.g.,
parkinsonism, bradykinesia, hypertonia, rigidity) were observed in
15% of tetrabenazine patients compared with 0% of placebo patients.
[0701] A Warning and Precaution cites the risk of dysphagia, an
underlying symptom of HD and a known side effect of reduced
dopaminergic neurotransmission. Although low rates of dysphagia
were reported in the 12-week trial, in open-label studies,
dysphagia was observed in 8% to 10% of tetrabenazine-treated
patients, with some cases associated with aspiration pneumonia. It
is unclear whether these cases were associated with treatment,
however FDA expressed concern that events of dysphagia, which can
have devastating clinical consequences, may have been significantly
underestimated in the tetrabenazine NDA. Of note, in a
retrospective study of 98 patients treated with tetrabenazine for
hyperkinetic movement disorders, dysphagia was observed in 19% of
patients. [0702] At 50 mg, tetrabenazine caused an approximately 8
ms mean increase in QTc interval (90% two-sided Confidence Interval
[CI]: 5.0, 10.4 ms).
[0703] The safety profile of tetrabenazine observed in the 12-week,
controlled trial is reflected in the prescribing information, as
summarized below.
TABLE-US-00013 TABLE 13 Treatment Emergent Adverse Reactions in
Patients Treated with Tetrabenazine Occurring with a Greater
Frequency than Placebo in 12-Week, Double-Blind, Placebo-Controlled
Trial of Tetrabenazine Tetrabenazine Placebo (N = 54) (N = 30) Body
System Preferred Term n (%) n (%) PSYCHIATRIC Sedation/somnolence
17 (31) 1 (3) DISORDERS Insomnia 12 (22) 0 Depression 10 (19) 0
Anxiety/anxiety 8 (15) 1 (3) aggravated Irritability 5 (9) 1 (3)
Appetite decreased 2 (4) 0 Obsessive reaction 2 (4) 0 CENTRAL &
Akathisia 10 (19) 0 PERIPHERAL Balance difficulty 5 (9) 0 NERVOUS
Parkinsonism/ 5 (9) 0 SYSTEM bradykinesia Dizziness 2 (4) 0
Dysarthria 2 (4) 0 Gait unsteady 2 (4) 0 Headache 2 (4) 1 (3)
GASTRO- Nausea 7 (13) 2 (7) INTESTINAL Vomiting 3 (6) 1 (3) SYSTEM
DISORDERS BODY AS Fatigue 12 (22) 4 (13) A WHOLE Fall 8 (15) 4 (13)
GENERAL Laceration (head) 3 (6) 0 Ecchymosis 3 (6) 0 RESPIRATORY
Upper respiratory 6 (11) 2 (7) SYSTEM tract infection DISORDERS
Shortness of 2 (4) 0 breath Bronchitis 2 (4) 0 URINARY Dysuria 2
(4) 0 SYSTEM DISORDERS
[0704] In comparison to deutetrabenazine, tetrabenazine appears to
produce more adverse effects.
ARC-HD
[0705] In a second clinical trial, a method for converting patients
with adequate control of chorea with tetrabenazine to
deutetrabenazine treatment was implemented. Alternatives for
Reducing Chorea in Huntington Disease (ARC-HD) was an open-label,
single-arm study in which subjects with manifest HD who were
receiving FDA-approved doses of tetrabenazine for the treatment of
chorea or had successfully completed First-HD were invited to
participate.
[0706] The study thus comprised two cohorts. The Rollover Cohort
(75 subjects) successfully completed the First-HD study described
above, including a 1-week washout; the Switch Cohort (37 subjects)
switched overnight from stable dosing (.gtoreq.8 weeks) with
tetrabenazine to deutetrabenazine based on a conversion method
designed to achieve comparable systemic exposure to total .alpha.
and .beta. metabolites. Other key inclusion criteria for the study
included: diagnosed with manifest HD, as indicated by
characteristic motor examination features; a documented expanded
cytosine adenine guanine (CAG) repeat (.gtoreq.37) and Total
Functional Capacity (TFC) score .gtoreq.5 at or before Screening;
able to ambulate without assistance for at least 20 yards
(assistive devices such as walker or cane permitted); and subject
has a reliable caregiver who interacts with the subject on a daily
basis, oversees study drug administration, assures attendance at
study visits, and participates in evaluations, as required. Key
exclusion criteria included serious untreated or undertreated
psychiatric illness (e.g., depression) at Screening or Baseline;
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 score .gtoreq.11 on the depression subscale of the
Hospital Anxiety and Depression Scale (HADS), a score of .gtoreq.11
on the Swallowing Disturbance Questionnaire (SDQ), or a Unified
Parkinson's Disease Rating Scale (UPDRS) dysarthria score of
.gtoreq.3 at Screening or Baseline.
[0707] Participants were 58% male, 95% White, and had a mean age of
54 years. The mean (SD) TMC score at Baseline was 12.2 (4.6) and
the mean (SD) CAG repeat length was 44 (3.7)
Study Design
[0708] The guidance for investigators on conversion of subjects
from stable doses of tetrabenazine to deutetrabenazine in the
ARC-HD Switch study was designed to minimize the risk that dose
conversion would result in either loss of efficacy or increased
adverse events. The conversion method applied was based on modeling
and simulation of Phase 1 pharmacokinetic data for deutetrabenazine
and tetrabenazine. The objective of the pharmacokinetic analysis
was to identify an initial dosing regimen of deutetrabenazine
predicted to provide exposure at steady state of the active .alpha.
and .beta. metabolites that was less than or equal to the predicted
AUC at steady state of the active alpha and beta metabolites of
tetrabenazine, but with a lower Cmax.
[0709] In a Phase 1 single-center, open-label, crossover clinical
trial, each of 24 healthy volunteer subjects received single doses
of 25 mg of tetrabenazine and 15 mg of deutetrabenazine. One of the
objectives of the clinical trial was to evaluate and compare the
safety of deutetrabenazine relative to tetrabenazine.
[0710] Subjects in the Switch cohort completed a full screening
evaluation. Subjects who were eligible to enroll in the study were
subsequently converted from their tetrabenazine dose regimen to a
deutetrabenazine dose regimen predicted to be comparable to their
existing tetrabenazine regimen. Subjects received existing
tetrabenazine regimen through midnight of Day 0 and switched to
their assigned deutetrabenazine regimen the next morning (Day 1 of
the study). The initial dose was based on a conversion method,
defined by a Phase 1 pharmacokinetic comparison of deutetrabenazine
and tetrabenazine suggesting an initial dose of deutetrabenazine
that is approximately 50% of the existing tetrabenazine dose (Table
15). Following the first week of deutetrabenazine treatment, the
dose of deutetrabenazine was allowed to be adjusted upward or
downward once per week in increments of 6 mg/day until a dose that
adequately controls chorea was identified, the subject experienced
a protocol defined "clinically significant" adverse event, or the
maximal allowable dose was reached. The investigator, in
consultation with the subject and caregiver, determined when an
adequate level of chorea control had been achieved. If a subject
experienced a "clinically significant" adverse event attributable
to deutetrabenazine, the investigator determined if a dose
reduction or suspension was necessary.
TABLE-US-00014 TABLE 15 Method for Converting Patients from
Tetrabenazine to deutetrabenazine Therapy Incoming Initial Initial
Total Daily Subsequent Total Daily Total Daily deutetrabenazine
deutetra- Tetra- deutetra- Dose Regimen benazine benazine benazine
Morning Evening Dosing Dose Dose Dose Dose Regimen 12.5 mg 6 mg 6
mg -- Dose adjusted 25 mg 12 mg 6 mg 6 mg upward or 37.5 mg 18 mg 9
mg 9 mg downward 50 mg 24 mg 12 mg 12 mg (6-mg/day 62.5 mg 30 mg 15
mg 15 mg increments 75 mg 36 mg 18 mg 18 mg once per week) 87.5 mg
42 mg 21 mg 21 mg to achieve 100 mg 48 mg 24 mg 24 g dose that
adequately controls chorea
[0711] Subjects in the Rollover cohort completed a 1-week washout
at the conclusion of First-HD, during which mean TMC scores
returned to baseline. The deutetrabenazine dose for these subjects
was titrated from a starting dose of 6 mg per day to a dose that
controlled chorea and was well tolerated.
[0712] For both cohorts, oral tablets at strengths of 6 mg, 9 mg,
and 12 mg were used. Doses of 12 mg and higher were administered in
two divided doses approximately 10 hours apart. All study treatment
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 CYP2D6 inhibitor (e.g., paroxetine),
in which case the maximum total daily dose was 36 mg.
[0713] Subjects attended regular clinic visits to evaluate safety
and establish an optimal dose. The investigator, in consultation
with the subject and caregiver, determined when an adequate level
of chorea control was achieved; the dose of DTBZ could be increased
on a weekly basis until there was adequate control of chorea, the
subject experienced a protocol defined clinically significant
adverse event, or the maximal allowable dose was reached. During
long-term treatment, all subjects had regular contact with the
study site for evaluation of safety and chorea control. Long-term
treatment will continue until deutetrabenazine becomes commercially
available in the U.S.
[0714] A total of 37 subjects with chorea associated with HD that
was adequately controlled with tetrabenazine who had converted from
tetrabenazine to deutetrabenazine treatment in ARC-HD Switch were
included in an analysis conducted to assess maintenance of chorea
control following dose conversion. The subjects included in the
analysis were each converted from tetrabenazine treatment to a
deutetrabenazine daily dose, administered twice daily, that was
approximately 30% to 50% of their prior total daily tetrabenazine
dose.
Results
[0715] Dose & Efficacy.
[0716] Given the differences in prior therapy and expected changes
in chorea control following initiation of deutetrabenazine therapy
in the two cohorts, efficacy data are summarized separately for
these two groups. Data from the two cohorts is provided below
through Week 15. As this study is ongoing, data from subsequent
weeks are still being gathered and analyzed, and results comprise
too few patients to draw meaningful conclusions at this stage.
[0717] Dose--Switch Cohort.
[0718] The mean dose of TBZ at baseline was 42 mg and, after the
overnight switch, the mean dose of deutetrabenazine was 20 mg. Mean
daily doses of deutetrabenazine following the switch from TBZ are
given below in Table 15.
TABLE-US-00015 TABLE 15 TBZ Dose at Baseline and DTBZ Dose
Conversion and Titration DTBZ Daily Dose (mg) TBZ Dose Day 1 at
Baseline through Statistic (mg) Week 1 Week 4 Week 8 Week 15 n 37
37 36 22 15 Mean (SD) 42.1 (19.58) 20.3 (10.23) 29.7 (10.44) 33.5
(11.36) 36.0 (14.70) Dose Minimum, 12.5, 100 6, 48 12, 48 12, 48
12, 60 Maximum
[0719] Dose--Rollover Cohort.
[0720] Mean daily doses of deutetrabenazine following wash-out and
initial doses of 6 mg/day are given below in Table 16.
TABLE-US-00016 TABLE 16 DTBZ Daily Dose Titration DTBZ Daily Dose
(mg) Statistic Week 2 Week 4 Week 8 Week 15 n 62 56 44 34 Mean (SD)
11.8 (1.07) 24.2 (4.57) 38.9 (11.09) 41.1 (9.24) Dose Minimum, 6,
12 6, 36 6, 48 18, 48 Maximum
[0721] Total Maximal Chores (TMC)--Switch Cohort.
[0722] One week following the switch to deutetrabenazine, at a time
when subjects were still receiving their initial total daily
deutetrabenazine dose, the mean total chorea score decreased by
approximately one point from baseline (mean.+-.standard error [SE]
change from baseline was -0.72.+-.2.6), indicating that
deutetrabenazine maintained chorea control in these subjects. A
subset of 35 subjects also had chorea assessed 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 from 21 patients were available at Week 8; these
data demonstrated change from baseline of -1.9.+-.3.5 units on the
TMC score; at week 15, -1.2.+-.4.1 units. Results are given below
in Table 17. A summary of the change in mean chorea score observed
and the mean daily dose of tetrabenazine or deutetrabenazine
corresponding to the chorea score is provided in FIG. 6.
TABLE-US-00017 TABLE 17 Total Maximal Chorea Score (Switch Cohort)
Total Maximal Chorea Score Mean (SD) Change Time Point n Mean (SD)
Score n from Baseline p-value.sup.a Baseline 37 12.47 (5.26) -- --
-- 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 Week 15 15 10.87 (5.99) 15 -1.17 (4.07) 0.2850
[0723] Total Maximal Chores (TMC)--Rollover Cohort.
[0724] At Week 2, a statistically significant mean (SD) decrease
from Baseline of 1.9 (3.0) units was observed (p<0.0001). This
effect persisted through Week 15, at which time the mean (SD)
decrease from baseline was 4.5 (5.0) units (p=0.0001). These
results are consistent with those observed for DTBZ in First-HD.
Results are given below in Table 18.
TABLE-US-00018 TABLE 18 Total Maximal Chorea Score (Rollover
Cohort) Total Maximal Chorea Score Mean (SD) Change Time Point n
Mean (SD) Score n from Baseline p-value.sup.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
[0725] Total Motor Score (TMS)--Switch Cohort.
[0726] Additionally, overall motor symptoms, as assessed by the
TMS, were maintained following dose conversion and appeared to
improve at Week 8, as indicated by a mean (SD) change from baseline
in TMS of -3.7 (7.8). Results are given below in Table 19.
TABLE-US-00019 TABLE 19 Total Motor Score Over Time (Switch Cohort)
Total Motor Score Mean (SD) Change Time Point n Mean (SD) Score n
from Baseline p-value.sup.a Baseline 37 38.49 (18.679) -- -- --
Week 1 37 36.35 (18.043) 37 -2.14 (5.414) 0.0218 Week 4 36 37.14
(19.516) 36 -1.85 (8.419) 0.1966 Week 8 24 34.58 (18.268) 24 -3.73
(7.787) 0.0279 Week 15 15 35.00 (22.984) 15 -1.93 (10.910)
0.5037
[0727] A summary of the change in mean chorea score observed and
the mean daily dose of tetrabenazine or deutetrabenazine
corresponding to the chorea score is provided in FIG. 7.
[0728] Total Motor Score (TMS)--Rollover Cohort.
[0729] Statistically significant mean decreases in TMS from
baseline were observed as early as Week 2 (3.9 units; p<0.0001)
and persisted through Week 15 (8.0 units; p=0.0001). Results are
given below in Table 20.
TABLE-US-00020 TABLE 20 Total Motor Score (Rollover Cohort) Total
Motor Score Mean (SD) Change Time Point n Mean (SD) Score n from
Baseline p-value.sup.a Baseline 71 35.3 (16.34) -- -- -- Week 2 61
32.4 (15.23) 58 -3.9 (6.67) <0.0001 Week 4 55 32.1 (16.84) 52
-5.9 (7.88) <0.0001 Week 8 43 31.0 (18.07) 40 -8.3 (8.58)
<0.0001 Week 15 35 30.5 (17.70) 33 -8.0 (8.41) <0.0001
[0730] The fact that the mean TMS improvement ((-3.7 units at Week
8 in the Switch cohort and -8.0 units at Week 15 in the Rollover
cohort) was greater in magnitude than the mean TMC score
improvement (-1.9 units at Week 8 in the Switch cohort and -4.5
units at Week 15 in the Rollover cohort) suggests a benefit of DTBZ
treatment on other motor symptoms of HD, in addition to the
reduction in chorea.
[0731] It is expected that other deuterium substituted
tetrabenazines and valbenazines will be efficacious in the
treatment of chorea and other symptoms associated with Huntington's
disease and other movement disorders, as well as abnormal
involuntary movements generally.
[0732] Adverse Events.
[0733] DTBZ was generally well tolerated, with safety results in
both the Rollover and Switch Cohorts consistent with the safety
profile observed in First-HD.
[0734] In the Rollover Cohort, 39 (52.0%) subject experienced AEs,
with the AEs assessed as mild or moderate in intensity in 36
(92.3%) of these 39 subjects. The most common AEs in the Rollover
Cohort were fall (10 subjects, [13%]), somnolence (6 [8%]),
depression (6 [8%]), and insomnia (6 [8%]). A similar percentage of
subjects in the Rollover Cohort experienced AEs from Day 1 through
Week 8 (45.3%) compared with Week 8 through the visit cut-off date
(43.2%). Five subjects had an AE that led to a dose reduction or
dose suspension. Three subjects experienced serious AEs (anxiety,
major depression, suicidal ideation, dehydration, encephalopathy,
and depression suicidal), with one of these serious AEs (major
depression) leading to study withdrawal. Three additional subjects
withdrew from the study due to an AE (worsening chorea, suicidal
ideation, and depression).
[0735] In the Switch Cohort, 21 (56.8%) subjects experienced at
least one AE, with AEs assessed as mild to moderate in intensity in
20 (95.2%) of the 21 subjects. The most common AEs in the Switch
Cohort were somnolence (9 subjects [24%]), anxiety (3 [8%]), and
fall (3 [8%]). The majority of these common events occurred during
the first 8 weeks of the study (22 Switch subjects had reached Week
8 by the visit cut-off date). The most common AEs occurred at
similar rates from Day 1 through Week 1, Week 2 through Week 4, and
Week 5 through Week 8. There were no adverse events of chorea or
worsening chorea during the reporting period, including the first
week after the conversion from tetrabenazine to deutetrabenazine.
Two subjects experienced serious AEs (pneumonia and dehydration),
no subjects withdrew from the study due to an AE, and four subjects
had an AE that led to a dose reduction or dose suspension.
[0736] There were no apparent increases in the overall incidence of
AEs in subjects with impaired CYP2D6 metabolism (including subjects
using a strong CYP2D6 inhibitor and CYP2D6 poor metabolizers).
[0737] Frequent treatment-emergent AEs, defined as events occurring
in at least 4% of subjects across all time periods in either
cohort, are summarized below in Table 21. The most common AEs
during the Entire Treatment Period in the Rollover Cohort were fall
(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 Switch Cohort were fall (3 subjects,
[8.1%]), somnolence (9 [24.3%], but most were transient and did not
require dose adjustment), depression (8 [10.7%]), and anxiety (3
[8.1%]). The types of common adverse events observed were
consistent with those observed with deutetrabenazine treatment in
First-HD. Falls are difficult to assess in this study population
with chorea and HD; the majority of the falls were not considered
to be related to study drug.
TABLE-US-00021 TABLE 21 TEAEs Occurring in at Least 4% of Subjects
in Either Cohort Rollover Cohort Switch Cohort (N = 75) (N = 37)
Event n (%) n (%) Fall 10 (13.3) 3 (8.1) Depressiona 8 (10.7) 2
(5.4) Somnolence 6 (8.0) 9 (24.3) Insomnia 6 (8.0) 1 (2.7)
Diarrhoea 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) Vomiting 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)
[0738] Additional Safety Measures.
[0739] Safety scales were incorporated into the study design to
monitor for subclinical toxicity associated with deutetrabenazine
treatment. These included observed values and changes in the UHDRS,
SDQ, UPDRS dysarthria question, Barnes Akathisia Rating Scale
(BARS), HADS, Epworth Sleepiness Scale (ESS), Columbia Suicide
Severity Rating Scale (C-SSRS), and Montreal Cognitive Assessment
(MoCA.RTM.). The overall analysis of the safety scales showed no
increased risk with deutetrabenazine treatment through Week 28 as
of the visit cut-off date for this study. Eight Rollover patients
had apparent decline in two of four cognitive measures (MoCA and
the verbal fluency task) at Week 28. These changes were often
associated with AEs (e.g., somnolence, fatigue, urinary tract
infection) and were typically not associated with reduced
performance on functional measures. No clinically relevant changes
in vital signs, ECGs, or clinical laboratory assessments were
observed during the study. Regarding body weight, from baseline
through Week 15, body weight increased in the Rollover cohort and
changed minimally in the Switch Cohort. Following Week 15, there
was a trend toward weight loss at Week 28 in both cohorts (Rollover
Cohort, 1.4 kg; Switch cohort 1.9 kg), however the decrease in the
number of subjects that reached the Week 28 milestone limits the
interpretation of these results.
[0740] Taken together, the results of this study support
deutetrabenazine as an effective therapeutic option, with a
favorable safety profile, for treatment of chorea associated with
HD. The results support the safety of an overnight switch from TBZ
to a predicted AUC-matched dose of deutetrabenazine, which can be
achieved without a loss of chorea control.
Tardive Dyskinesia
[0741] An open-label, single-arm study in which 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 efficacy of long-term maintenance therapy of
deutetrabenazine to reduce the severity of abnormal involuntary
movements of TD.
[0742] Study Design.
[0743] Inclusion criteria included: at least 18 years of age;
successful completion of prior deutetrabenazine controlled study
for treatment of moderate to severe TD; history of using a dopamine
receptor antagonist for at least 3 months (or 1 month in subjects
60 years of age and older); clinical diagnosis of TD and has had
symptoms for at least 3 months; for subjects with underlying
psychiatric illness: [0744] psychiatrically stable and no change in
psychoactive medications for .gtoreq.30 days before screening (45
days for antidepressants); [0745] subjects on long acting (depot)
medications have been on stable therapy (dose, frequency) for
.gtoreq.3 months before Screening; and [0746] subject has a mental
health provider who is aware of the subject's participation in the
trial and does not anticipate any changes to the subject's
treatment regimen (drug, dose, frequency) in the next 3 months;
[0747] history of being compliant with prescribed medications; able
to swallow study drug whole; lives in a stable environment, and has
adequate supervision when necessary to comply with all study
procedures, attend all study visits, and safely participate in the
trial; sufficient reading skills to comprehend the
subject-completed rating scales; female subjects of childbearing
potential agree to use one of the following acceptable methods of
contraception from screening through study completion if sexually
active: [0748] IUD or intrauterine system in place for at least 3
months prior to screening; [0749] Subject or partner using barrier
method with spermicide from screening through study completion;
[0750] Partner has a documented vasectomy >6 months prior to
enrollment; or [0751] Stable hormonal contraception (with approved
oral, transdermal, or depot regimen) for at least 3 months prior to
screening,
[0752] Exclusion criteria included: subject has received
tetrabenazine within 7 days of baseline, or any of the following
medications within 30 days of Baseline: reserpine,
.alpha.-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months
of Baseline), and medications 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
(MAOIs), levodopa or dopamine agonists; subject has a neurological
condition other than TD that may interfere with assessing the
severity of dyskinesias; serious untreated or undertreated
psychiatric illness at baseline; active suicidal ideation at
baseline; history of any of the following within 6 months of
Baseline: previous intent to act on suicidal ideation with a
specific plan (positive answer to question 5 on C-SSRS)
irrespective of level of ambivalence at the time of suicidal
thought, previous preparatory acts to commit suicide or suicidal
behavior, or previous actual, interrupted, or aborted suicide
attempt; score .gtoreq.11 on the depression subscale of the
Hospital Anxiety and Depression Scale (HADS) at baseline; subject
is developmentally disabled or has evidence of dementia; subject
has an unstable or serious medical illness at baseline; history
(within 3 months) or presence of violent behavior; QTcF value
>450 ms (males) or >460 ms (females), or >480 ms (with
right bundle branch block [RBBB]) on 12-lead electrocardiogram
(ECG) at baseline; evidence of hepatic impairment at Screening, as
indicated by: aspartate transaminase (AST) or alanine
aminotransferase (ALT) >2.5 times the upper limit of normal
(ULN), alkaline phosphatase (ALP) or total bilirubin (TBil) >2
times the ULN (but subjects with Gilbert's Syndrome are eligible to
participate if approved by the medical monitor, and subjects with
abnormalities in two or more of these analytes (AST, ALT, ALP,
TBil) must be approved by the Medical Monitor to be enrolled), and
prothrombin time >4 sec prolonged; positive Hepatitis B surface
antigen (HBsAg); evidence of significant renal impairment at
Screening, indicated by a creatinine clearance <50 mL/min, as
estimated by the Cockroft-Gault formula; known allergy to
tetrabenazine or to any of the components of deutetrabenazine; has
participated in an investigational drug or device trial (other than
eligible deutetrabenazine study) and received study drug within 30
days (or 5 drug half-lives) of baseline, whichever is longer;
subject is pregnant or breast-feeding at baseline; and present use
of illicit drugs at baseline.
[0753] Dose Regimen.
[0754] Deutetrabenazine tablets were provided in dosage strengths
of 6, 9, 12, 15, and 18 mg. During dose adjustment/titration,
deutetrabenazine was supplied in weekly blister cards. During
long-term treatment, deutetrabenazine will be supplied in 30-count
bottles. Study drug were administered as follows. All treatment
regimens were administered twice daily (BID) with meals,
approximately 10 hours apart during the day. The starting dose was
deutetrabenazine 12 mg/day (6 mg BID) regardless of previous
treatment in the parent trial. Prior treatment assignment from the
parent trial remained blinded. The maximum total daily dose of
deutetrabenazine was 48 mg/day (24 mg BID) unless the subject is on
a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion),
in which case the maximum total daily dose is 36 mg/day. Daily
doses up to 36 mg/day were given as one tablet BID whereas daily
doses of 42 mg/day and 48 mg/day were given as two tablets BID.
During the titration period, the dose of deutetrabenazine should be
increased on a weekly basis in increments of 6 mg per day until 1)
there was adequate control of dyskinesia; 2) the subject
experienced a protocol defined clinically significant AE (defined
as related to study drug and either a) moderate or severe in
intensity or b) meets the criteria for a SAE); or 3) the maximal
allowable dose was reached. If a subject experienced a clinically
significant AE attributable to deutetrabenazine, the Investigator
determined if a dose reduction or suspension was necessary.
[0755] Long-Term Treatment.
[0756] For all subjects participating in the Long-Term Treatment
Period, the dose of deutetrabenazine may be adjusted (upward or
downward) in increments of 6 mg per day, if necessary, to optimize
dyskinesia control while minimizing AEs. However, such changes in
dose may not occur more frequently than once per week.
[0757] Titration Period (Up to 6 Weeks).
[0758] Subjects who successfully completed a parent study were
eligible to enroll into this study after a 1-week washout period
and the final evaluation. As subjects had discontinued study drug
or placebo for 1 week, they underwent deutetrabenazine dose
titration in this study. During titration, the investigator, in
consultation with the subject determined when an adequate level of
dyskinesia control had been achieved. The dose of deutetrabenazine
was adjusted (upward or downward) in increments of 6 mg per day up
to once per week, until adequate control of dyskinesia was
achieved, a clinically significant adverse event related to study
drug (either a) moderate or severe in intensity or b) a serious
adverse event) occurred, or the maximal allowable dose is reached.
If a subject experienced a clinically significant AE attributable
to deutetrabenazine, the investigator determined if a dose
reduction or suspension was necessary. Subjects had a telephone
contact at Week 1 and a clinic visit at Week 2, to evaluate safety
and establish a dose of study drug that adequately controlled
dyskinesia and was well tolerated. Although subjects entered the
long-term treatment period after Week 2, titration continued
through Week 6 to optimize dose.
[0759] Long-Term Treatment Period (Up to 52 Weeks).
[0760] During long-term treatment, subjects will continue titration
through Week 6. During this period, all subjects will be contacted
by telephone at Week 3 (the 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 evaluation of safety and dyskinesia control.
Subjects who have not achieved a dose level that adequately
controls dyskinesia and is well tolerated by the Week 6 visit
should have unscheduled visits or telephone contacts to further
adjust their dose upward or downward. Interactions with the
clinical site for dose adjustment should alternate between
telephone contacts and clinic visits. During long-term treatment,
further dose adjustments of deutetrabenazine may be made, if
necessary, but not more often than weekly and only in increments of
6 mg per day. Dose adjustments should be based on all available
information, including the subject's and caregiver's (if
appropriate) reports of AEs and dyskinesia control, as well as
information from rating scales and safety evaluations, when
available.
[0761] Post-Treatment Safety Follow Up.
[0762] All subjects will discontinue study drug at the Week 54
visit and return for their final clinic visit at Week 55 for
evaluation of safety, dyskinesia control, and motor function.
During this 1-week washout period, subjects should not take
prohibited concomitant medications. Subjects will also have a
follow-up telephone contact at Week 58, four weeks after their last
dose of study drug, to evaluate AEs and concomitant medication
usage.
[0763] Safety Endpoints.
[0764] 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 ECGs, Unified Parkinson's Disease Rating Scale (UPDRS) Part
III (motor examination), Barnes Akathisia Rating Scale (BARS),
Hospital Anxiety and Depression Scale (HADS), Columbia Suicide
Severity Rating Scale (C-SSRS), Epworth Sleepiness Scale (ESS), and
Montreal Cognitive Assessment (MoCA.RTM.).
[0765] Efficacy Endpoints.
[0766] The following measures were or will be used to assess
efficacy: change in Abnormal Involuntary Movement Scale (AIMS)
score (items 1 through 7) from baseline to end of long-term therapy
(Week 54) as assessed by blinded central video rating; proportion
of subjects who are a treatment success at the end of long-term
therapy (Week 54), based on the Clinical Global Impression of
Change (CGIC) (in which a treatment success is defined as Much or
Very Much Improved); change in the modified Craniocervical Dystonia
(CDQ-24) score from baseline of this study to the end of long-term
therapy (Week 54); proportion of subjects who have a 50% or greater
reduction in AIMS score from baseline of this study to the end of
long term therapy (Week 54); proportion of subjects who are a
treatment success at the end of long-term therapy (Week 54), based
on the Patient Global Impression of Change (PGIC) (in which a
treatment success is defined as Much or Very Much Improved);
percent change in AIMS score from Baseline of this study to the end
of long term therapy (Week 54); and based on the change in AIMS
score from baseline of this study to the end of long-term therapy
(Week 54), as assessed by blinded central video rating, the
cumulative proportion of responders ranging from a 10% improvement
from baseline to a 90% improvement from baseline in steps of 10
percentage points.
[0767] Results.
[0768] Results are given in FIG. 9, which shows that by Week 6 of
the study, over 50% of subjects were much or very much improved
according to PGIC and CGIC.
ARM-TD
[0769] An additional clinical study, Aim to Reduce Movements 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-group study
of 117 patients globally (with 104 patients completing the trial)
with moderate to severe tardive dyskinesia.
[0770] Subjects were screened for inclusion in the study as
follows. Inclusion criteria included: between 18 and 75 years of
age, inclusive; history of using a dopamine receptor antagonist for
at least 3 months (or 1 month in subjects 60 years of age and
older); clinical diagnosis of TD, and has had symptoms for at least
3 months prior to Screening; TD symptoms are bothersome to the
subject or cause functional impairment; at Screening and Baseline
visits, the subject has moderate or severe abnormal movements as
judged by the Investigator based on Item 8 of the AIMS and a total
motor AIMS score of .gtoreq.6 (based on Items 1 through 7) as
assessed by the Principal Investigator; for subjects with
underlying psychiatric illness, subject is psychiatrically stable
and has had no change in psychoactive medications (including, but
not limited to neuroleptics, benzodiazepines, anticonvulsants, and
mood stabilizers) for .gtoreq.30 days before Screening (45 days for
antidepressants); subjects on long-acting (depot) medications have
been on stable therapy (dose, frequency) for .gtoreq.3 months
before Screening; and subject has a mental health provider who is
aware of the subject's participation in the trial, and does not
anticipate any changes to the subject's treatment regimen (drug,
dose, frequency) in the next 3 months; history of being compliant
with prescribed medications; able to swallow study drug whole;
written, informed consent; subject has good general health, lives
in a stable environment, is expected to complete all study
assessments, and has adequate supervision when necessary to comply
with all study procedures, attend all study visits and safely
participate in the trial; sufficient reading skills to comprehend
the subject-completed rating scales; and, if female and of
childbearing potential, agree to use acceptable methods of
contraception from Screening through study completion if sexually
active.
[0771] Exclusion criteria included: score .gtoreq.11 on the
depression subscale of the Hospital Anxiety and Depression Scale
(HADS) at Screening or Baseline; developmentally disabled or has
evidence of dementia; unstable or serious medical illness at
Screening or Baseline; history (within 3 months) or presence of
violent behavior; QTcF value >450 ms (males) or >460 ms
(females), or >480 ms (with right bundle branch block [RBBB]) on
12-lead ECG at Screening; evidence of hepatic impairment at
Screening, as indicated by: AST or ALT >2.5 times the upper
limit of normal (ULN), or ALP or total bilirubin >2 times the
ULN (wherein abnormalities in two or more of these AST, ALT, ALP,
TBil must be approved by the Medical Monitor to be enrolled, but
subjects with Gilbert's Syndrome eligible if approved by the
Medical Monitor), or Prothrombin time >4 seconds prolonged, or
positive HBsAg; evidence of significant renal impairment at
Screening, indicated by a creatinine clearance <50 mL/min, as
estimated by the Cockroft-Gault formula; known allergy to
tetrabenazine or to any of the components of deutetrabenazine;
subject has participated in an investigational drug or device trial
and received study drug within 30 days (or 5 drug half-lives) of
Screening, whichever is longer; pregnant or breast-feeding at
Screening or Baseline; acknowledged present use of illicit drugs at
Screening; history of alcohol or substance abuse in the previous 12
months, as defined in the DSM-V, or subject is unable to refrain
from substance abuse throughout the study; and positive urine drug
screen (for amphetamines, barbiturates, benzodiazepine,
phencyclidine, cocaine, or opiates) at Screening or Baseline,
except if subject is receiving a stable dose of a
benzodiazepine.
[0772] Dosing.
[0773] Enrolled patients received either deutetrabenazine or
placebo, which was titrated from a starting dose of 6 mg of
deutetrabenazine (which, as in previous studies, provides an AUC of
total (.alpha.+.beta.)-HTBZ that is comparable to 12.5 mg of
tetrabenazine) to optimal dosage between 12 and 48 mg/day over the
course of six weeks, in increments of 6 mg/day per week. Drug was
then administered at that dose for another six weeks for a total
treatment of 12 weeks, followed by a 1-week washout period.
Randomization to each group was 1:1 and was stratified by baseline
use of dopamine receptor antagonists (currently taking versus not).
Deutetrabenazine tablets or placebo, were supplied as 6, 9, 12, 15,
and 18 mg tablets and administered BID with meals in the morning
and evening (recommended 10 hours apart; minimum 6 hours apart).
Dose suspensions of up to one week were permitted if the subject
experienced a clinically significant adverse event.
[0774] Study Objectives and Endpoints.
[0775] The objectives of the study was to evaluate the efficacy of
SD-809 in reducing the severity of abnormal involuntary movements
associated with tardive dyskinesia and the safety and tolerability
of titration and maintenance therapy with deutetrabenazine in
subjects with drug-induced tardive dyskinesia. The primary efficacy
endpoint is the change in AIMS score (Items 1 through 7) from
baseline to Week 12, as assessed by blinded central video rating.
Baseline AIMS score is defined for each subject as the Day 0
assessment. The AIMS is composed of 12 clinician-administered and
scored items. Items 1-10 are rated on a 5-point, anchored scale and
consist of the following: [0776] Items 1-4 assess orofacial
movements; [0777] Items 5-7 deal with extremity and truncal
dyskinesia; [0778] Items 8-10 deal with global severity as judged
by the examiner, and the patient's awareness of the movements and
the distress associated with them; and [0779] Items 11-12 are
yes/no questions concerning problems associated with teeth and/or
dentures, as such problems can be mistaken for dyskinesia.
[0780] A total score from items 1 through 7 (orofacial, extremity
and truncal movements) can be calculated and represent observed
movements, with higher scores indicative of more severe dyskinesia.
Item 8 can be used as an overall severity index; items 9 and 10
provide additional information with regard to patient
incapacitation and awareness; and items 11 and 12 provide
information that may be useful in determining lip, jaw, and tongue
movements.
[0781] The key secondary endpoints are: 1) the proportion of
subjects who are a treatment success at Week 12, based on the
Clinical Global Impression of Change (CGIC); 2) the proportion of
subjects who are a treatment success at Week 12, based on the
Patient Global Impression of Change (PGIC); and 3) the change in
the modified Craniocervical Dystonia Questionnaire (CDQ-24) from
baseline to Week 12. As with previous studies, PGIC/CGIC treatment
success may be defined as Much or Very Much Improved on a 7-point
Likert Scale, ranging from very much worse to very much improved at
Week 12. The CDQ-24 is a disease-specific quality of life
questionnaire developed for use in patients with craniocervical
dystonia, including both cervical dystonia (CD) and blepharospasm
(BPS). The CDQ-24 was selected for use in the present study because
it includes domains which are relevant not only to CD and BPS, but
to TD, such as stigma, emotional well-being, pain, activities of
daily living, and social/family life. For the present study, the
CDQ-24 has been modified such that the questions focus more
directly on the impact of TD (as opposed to CD/BPS) on quality of
life.
[0782] Additional secondary endpoints included 1) the percent
change in AIMS score (central rating) from baseline to Week 12; 2)
based on the change in AIMS score (central rating) from baseline to
Week 12, the cumulative proportion of responders for responder
levels ranging from a 10% improvement from baseline to a 90%
improvement from baseline in steps of 10 percentage points; and 3)
Change in AIMS score (Items 1 through 7) from baseline to Week 12,
as assessed by the local rater, wherein baseline AIMS score is
defined for each subject as the Day 0 assessment.
[0783] Finally, at each clinical site, an Investigator experienced
in assessing movement disorders, was responsible for confirming the
diagnosis of TD, performing all clinical assessments, and making
decisions about adjusting the dose of study drug. Safety was also
monitored via adverse events reporting and other measures,
including but not limited to the UPDRS, BARS, HADS, C-SSRS, ESS,
and MoCA.
[0784] Measurements and Statistics.
[0785] Digital video recordings of AIMS assessments made at all
clinic visits (at Screening, Baseline, Weeks 2, 4, 6, 9, and 12)
were rated by pairs of central raters who were experts in movement
disorders and were blinded to treatment arm, sequence of video, and
the investigator AIMS score. Analysis was carried out using a
linear mixed model for repeated measurements (MMRM) with the change
in the AIMS score as the dependent variable. The model included
fixed effects for treatment group, time point (five levels: Weeks
2, 4, 6, 9, and 12), the treatment group by time point interaction,
and the randomization stratification variable. The unstructured
covariance model was used and the primary analysis compared the
deutetrabenazine and placebo groups at Week 12 using a two-sided
test at the 5% level of significance.
[0786] Efficacy Results.
[0787] Top-line data showed that the study met its primary
endpoint. Patients taking deutetrabenazine achieved an improvement
of 3.0 points on the AIMS score from baseline to end of therapy
compared to 1.6 points in placebo (p=0.0188) for a clinically
meaningful effect. Additionally, secondary endpoints numerically
favored deutetrabenazine. Results are given in Table 22,
TABLE-US-00022 TABLE 22 DTBZ Placebo Treatment (N = 56) (N = 57)
Difference AIMS Change (LS Mean) -3 -1.6 -1.4 (p-value 0.0188) PGIC
Treatment Success 42.90% 29.80% 13.00% N (%) CGIC Treatment Success
48.20% 40.40% 7.90% (%) Change from baseline -11.1 -8.3 -2.7
mCDQ-24*
[0788] Safety Results.
[0789] The study also showed a favorable safety and tolerability
profile for deutetrabenazine, including low rates of depression,
somnolence, insomnia and akathisia. Fewer patients taking
deutetrabenazine than placebo experienced serious adverse events
(SAEs) (4 patients [6.9%] in deutetrabenazine versus 6 [10.2%] in
placebo; none of the SAEs were treatment related) or experienced
adverse events leading to discontinuation (1 patient [1.7%] versus
2 patients [3.4%]). Neuropsychiatric adverse events in this patient
population were infrequently associated with SD-809 treatment
compared to placebo, and included somnolence/sedation (9 [15.5%]
versus 6 [10.2%]), insomnia (4 [6.9%] versus 1 [1.7%]), akathisia
(3 [5.2%] versus 0 [0.0%]) (Depression/depressed mood was reported
by one patient in each treatment group, and suicidal ideation was
reported by one patient in the placebo group versus none in the
SD-809 group. Three patients discontinued from the study for
adverse events (1 in deutetrabenazine group vs. 2 in placebo
group). For all other side effects reported in the study, rates in
the deutetrabenazine group were similar or lower than the placebo
group. Results are shown below in Table 23, which includes adverse
events observed in 3 or more subjects.
TABLE-US-00023 TABLE 23 DTBZ Placebo (n = 58) (n = 59) Any TEAEs
(Treatment-Emergent 41 (70.7%) 36 (61.0%) Adverse Events) Serious
TEAEs 4 (6.9%) 6 (10.2%) TEAEs Resulting in Study Withdrawal 1
(1.7%) 2 (3.4%) Nervous system Somnolence/sedation 9 (15.5%) 6
(10.2%) disorders Headache 4 (6.9%) 6 (10.2%) Dizziness 2 (3.4%) 3
(5.1%) Akathisia 3 (5.2%) 0 (0.0%) Psychiatric Anxiety 3 (5.2%) 4
(6.8%) disorders Insomnia 4 (6.9%) 1 (1.7%) Gastrointestinal Dry
mouth 2 (3.4%) 6 (10.2%) disorders Diarrhea 3 (5.2%) 3 (5.1%)
Constipation 2 (3.4%) 2 (3.4%) Nausea 2 (3.4%) 2 (3.4%) Vomiting 1
(1.7%) 3 (5.1%) General disorders Fatigue 4 (6.9%) 5 (8.5%) Chest
pain 1 (1.7%) 2 (3.4%) Infections and Upper respiratory 2 (3.4%) 4
(6.8%) infestations tract infection Nasopharyngitis 2 (3.4%) 1
(1.7%) Pneumonia 1 (1.7%) 2 (3.4%)
[0790] Based on the studies disclosed herein, it is expected that
deutetrabenazine, other deuterium substituted tetrabenazines and
valbenazine will be efficacious in the treatment of tardive
dyskinesia and other movement disorders and symptoms, such as
dyskinesias generally, dystonia, ballismus, akinesia, and
parkinsonism, and that the dosing regimens and methods disclosed
herein will yield significant patient benefits.
Tourette Syndrome
[0791] Tourette syndrome (TS) is a neurological disorder
characterized by repetitive, stereotyped, involuntary movements and
vocalizations called tics, which per DSM-V criteria first presents
in childhood, before 18 years of age. Several studies have been or
could be used to demonstrate the efficacy and tolerability of
deutetrabenazine in the reduction of symptoms associated with TS,
including motor and phonic tics.
Open-Label Pilot Study of Safety and Efficacy in TS Patients
[0792] An open-label, pilot study was undertaken 1) to evaluate the
safety and tolerability of treatment with deutetrabenazine, and 2)
to evaluate the efficacy of deutetrabenazine to suppress the motor
and phonic tics of TS.
[0793] Study Design.
[0794] Inclusion criteria (at screening, unless otherwise
indicated) included: 12 to 18 years of age, inclusive; DSM-V
diagnosis of TS and has manifested motor and phonic tics within 3
months before screening; total tic score of 19 or higher on the
YGTSS; TS-CGI score of 4 or higher (consistent with moderately
ill); tic severity and frequency has been stable for at least 2
weeks; able to swallow study medication whole; willing to adhere to
medication regimen and to comply with all procedures; in good
general health, as indicated by medical and psychiatric history as
well as physical and neurological examination; written, informed
consent (subject and parent/guardian); and female subjects of
childbearing potential agree to use an acceptable method of
contraception through study completion, including abstinence, IUD
or intrauterine system in place for at least 3 months prior;
subject or partner using barrier method (e.g., condom, diaphragm,
or cervical cap) with spermicide; partner has a documented
vasectomy >6 months prior to enrollment; stable hormonal
contraception (with approved oral, transdermal, or depot regimen)
for at least 3 months prior.
[0795] Exclusion criteria (at screening or baseline, unless
otherwise indicated) included: serious untreated or undertreated
psychiatric illness, such as depression, schizophrenia, or bipolar
disorder (but subjects receiving antidepressant therapy may be
enrolled if on a stable dose for at least 8 weeks before); history
of suicidal thoughts or behavior, including previous intent to act
on suicidal ideation with a specific plan (positive answer to
question 5 on the Columbia Suicide Severity Rating Scale [C-SSRS])
irrespective of level of ambivalence at the time of suicidal
thought, previous preparatory acts or behavior, or previous actual,
interrupted, or aborted suicide attempt; subject has received any
of the following concomitant medications within 14 days prior to
screening or baseline: tetrabenazine, neuroleptics (oral or depot,
typical and atypical; depot\within 3 months of screening),
guanfacine or clonidine (within 7 days of screening or baseline),
benzodiazepines such as clonazepam, topiramate, metoclopramide,
monoamine oxidase inhibitors (MAOIs), levodopa or dopamine
agonists, reserpine (within 21 days of screening or baseline),
botulinum toxin (within 3 months of screening or baseline); subject
is being treated with deep brain stimulation for control of tics;
below-average intelligence or mental abilities, in the opinion of
the Investigator; progressive or degenerative neurological disorder
or a structural disorder of the brain; subject receiving more than
one agent for the treatment of each co-morbid behavioral symptom;
subject requires treatment with drugs known to prolong the QT
interval (but citalopram and escitalopram allowed when administered
according to approved labeling); QTcF value >440 ms on 12-lead
electrocardiogram (ECG); known allergy to any of the components of
study medication; participation in an investigational drug or
device trial within 30 days (or 5 drug half-lives) of screening,
whichever is longer; pregnant or breast-feeding; present use of
illicit drugs; and history of alcohol or substance abuse in the
previous 12 months, as defined in the DSM-V, or unable to refrain
from substance abuse throughout the study.
[0796] Subjects completing the trial received treatment with study
drug for a total of 8 weeks and had safety follow-up 4 weeks after
treatment. Throughout the study, an independent rater assessed tic
severity with the Yale Global Tic Severity Scale (YGTSS) and tic
impact with the TS-Clinical Global Impression (TS-CGI) scale. The
independent rater will not have knowledge of the subject's clinical
care, including medications or reports of adverse events (AEs).
[0797] Dose Regimen.
[0798] Study drug was available in five dose strengths: 6, 9, 12,
15, and 18 mg, all of which were identical in size, shape, and
color (white). Subjects who qualified for the study were assigned
to treatment with deutetrabenazine and were titrated over 6 weeks
to a dose level of study drug that adequately suppressed tics and
was well tolerated (i.e., optimal dose). Subjects then maintained
that dose level for the duration of the treatment period. Subjects
who were receiving CBIT (Comprehensive Behavioral Intervention for
Tics) therapy were permitted to participate as long as therapy had
been stable/ongoing for at least 4 weeks before Screening and was
expected to be stable for the duration of the trial. Study drug was
dosed as follows. All treatment doses were administered with meals.
A daily dose of 6 mg was given once a day in the morning, and daily
doses of 12 mg and higher were administered twice daily in divided
doses, approximately 10 hours apart during the day. The starting
dose was deutetrabenazine 6 mg in the AM. The dose of study drug
was optionally adjusted weekly in increments of 6 mg/day during the
titration period to identify a dose level that suppressed tics and
was well tolerated. Dose reductions were in increments of 6 mg/day.
In this study, the maximum total daily dose of deutetrabenazine at
the Week 5 visit or later was 36 mg (18 mg twice daily [BID]).
[0799] Screening/Baseline Visit.
[0800] After informed consent/written assent was obtained, subjects
who met selection criteria had a comprehensive evaluation including
physical and neurological examination. Subjects then underwent a
baseline assessment of tic severity (performed by an independent
rater) and co-morbid illnesses. Following this evaluation, subjects
continuing to meet selection criteria were provided with
deutetrabenazine and were instructed to start treatment on Day 1,
the day after the baseline visit.
[0801] Titration Period (6 Weeks).
[0802] Subjects and their parent/guardian interacted weekly with
the clinical research staff, either by telephone contact or clinic
visit, through the sixth week of the titration period, in order to
evaluate safety and establish a dose of deutetrabenazine that
adequately suppressed tics and was well tolerated. Safety
evaluations during titration included assessment of vital signs,
monitoring for adverse events, and rating scales for depression and
suicidal ideation and behavior. In-person study visits were
scheduled at Weeks 2 and 4 after initiating therapy and telephone
contacts were scheduled for Weeks 1, 3, 5, and 6 after initiating
therapy in order to assess tic suppression and adverse events. The
YGTSS and TS-CGI were assessed by an independent rater. The
Investigator, in consultation with the subject and parent/guardian,
determined when an adequate level of tic suppression had been
achieved. The dose of deutetrabenazine was increased on a weekly
basis until there was adequate suppression of tics, the subject
experienced a protocol-defined "clinically significant" AE (defined
as an AE that is related to study medication and either (1)
moderate or severe in intensity or (2) meets the criteria for a
serious adverse event [SAE]), or the maximal allowable dose was
reached. Although dose adjustments could made up to and including
the Week 5 phone call, if a stable dose was reached before then,
the subject continued on that dose for the remainder of the
titration period and throughout maintenance dosing. Once adequate
suppression of tics had been achieved, the dose of study drug was
not increased further. If a subject experienced a "clinically
significant" AE that was attributed to study drug, the Investigator
used his or her judgment to determine if a dose reduction or
suspension was necessary. Dose adjustments were to be made based on
all available information, including the subject and
parent/guardian reports of AEs and tic suppression, the clinical
assessment of safety and efficacy by the Investigator, as well as
information from rating scales. At the end of the titration period,
the subject's dose was established for the maintenance period.
[0803] Maintenance Period (2 Weeks).
[0804] Subjects continued to receive their maintenance dose over
the next 2 weeks, although dose reductions for AEs were allowed.
Subjects returned to the clinic at Week 8 for a complete
evaluation, including physical and neurological examination and
performance of all rating scales, including the YGTSS and TS-CGI,
which were assessed by an independent rater. Subjects discontinued
study drug at the Week 8 visit.
[0805] Follow-Up (4 Weeks).
[0806] Subjects returned 1 week after the Week 8 visit for
evaluation of safety and tic suppression. Subjects also had a
follow-up telephone contact 4 weeks after their last dose of study
drug. Subjects who completed the study were potentially eligible to
participate in a long-term safety study if such a study were
conducted.
[0807] Pharmacokinetics.
[0808] A PK substudy was conducted to evaluate the PK of
deutetrabenazine and its metabolites in up to 9 of the 21 enrolled
subjects. Subjects in the PK substudy underwent sequential PK blood
sampling over the course of 6 hours postdose at the Week 8 visit.
For the subjects not participating in the PK substudy, a single PK
sample was obtained at Week 8 at the time of the blood draw for
clinical laboratory tests.
[0809] Safety Endpoints.
[0810] Safety and tolerability were assessed throughout the study
by monitoring the following parameters: adverse events (AEs),
clinical laboratory tests, physical examination, vital signs,
12-lead ECGs, Columbia Suicide Severity Rating Scale (C-SSRS), Beck
Depression Inventory, Second Version (BDI-II), and the Children's
Yale-Brown Obsessive-Compulsive Scale (CY-BOCS).
[0811] Efficacy Endpoints.
[0812] The following measures were used to assess efficacy: Yale
Global Tic Severity Scale (YGTSS), Total Tic Severity Score (TTS)
of the YGTSS, Global Severity Score (GSS) of the YGTSS, Tourette
Syndrome Clinical Global Impression (TS-CGI), and Tourette Syndrome
Patient Global Impression of Change (TS-PGIC).
[0813] Results.
[0814] Initial results indicate that deutetrabenazine is
efficacious in the treatment of tics associated with Tourette
syndrome. A consistent trend of improvement was observed in motor,
vocal, total tic severity, and Yale global total tic severity from
baseline through the end of the eight-week treatment phase. This
culminated in a mean change of -10.4 units in total tic severity.
Additionally, discontinuation in treatment after week 8 led to a
slight increase in tics. Results are given below in Table 24; ND
indicates no data.
TABLE-US-00024 TABLE 24 Overall (N = 23) Visit MTSS VTSS TTS
Impairment GSS B* n 23 23 23 23 23 Mean 17.4 14.2 31.6 34.3 66.0
(SD) (3.95) (5.66) (7.92) (9.45) (15.99) Median 18 15 31 30 68 Min,
Max 10, 24 0, 22 19, 46 20, 50 39, 96 Wk 2 n 21 21 21 ND 21 Mean
15.9 13.5 29.4 ND 59.4 (SD) (5.06) (5.64) (9.81) (19.45) Median 16
14 28 ND 57 Min, Max 0, 24 4, 22 4, 46 ND 4, 96 .DELTA. B- n 21 21
21 ND 21 Wk 2 Mean -1.9 -1.0 -2.9 ND -7.7 (SD) (2.67) (3.29) (5.37)
(12.25) Median 0 0 0 ND 0 Min, Max -10, 0 -11, 4 -21, 4 ND -41, 12
Wk 4 n 21 21 21 ND 21 Mean 14.2 12.1 26.3 ND 51.1 (SD) (6.30)
(6.60) (11.91) (22.64) Median 14 12 27 ND 51 Min, Max 0, 25 0, 25
0, 50 ND 0, 100 .DELTA. B- n 21 21 21 ND 21 Wk 24 Mean -3.5 -2.5
-6.0 ND -16.0 (SD) (4.32) (4.55) (8.18) (18.84) Median -2 0 -3 ND
-12 Min, Max -15, 2 -12, 4 -25, 4 ND -55, 4 Wk 8 n 23 23 23 21 23
Mean 12.0 9.2 21.2 22.9 45.1 (SD) (5.35) (6.64) (10.95) (11.46)
(21.71) Median 11 9 23 20 47 Min, Max 0, 24 0, 24 0, 48 0-50 0, 98
.DELTA. B- n 23 23 23 21 23 Wk 28 Mean -5.3 -5.0 -10.4 -11.9 -20.8
(SD) (4.98) (4.41) (8.83) (9.28) (17.61) Median -4 -4 -10 -10 -16
Min, Max -15, 6 -14, 2 -25, 5 -30-0 -50, 15 Wk 9 n 18 18 18 ND 18
Mean 13.9 11.7 25.6 ND 51.7 (SD) (4.94) (7.30) (11.06) (22.98)
Median 14.5 10.5 26 ND 51 Min, Max 5, 25 0, 25 10, 50 ND 14, 100
.DELTA. B- n 18 18 18 ND 18 Wk 9 Mean -3.4 -2.9 -6.3 ND -14.7 (SD)
(3.15) (3.80) (6.49) (15.50) Median -3 -2.5 -5 ND -10.5 Min, Max
-11, 1 -11, 3 -22, 4 ND -45, 4 *B = baseline; Wk = week
[0815] Additionally, preliminary results indicate improvements in
several other relevant measures. In PGIC, a mean improvement of 1.8
points was observed (on the 7-point scale above where 1=minimally
improved, 2=much improved, 3=very much improved), suggesting
patients are generally improved after 8 weeks of treatment (about
75% much or very much improved). In TS-CGI, mean improvement from a
baseline of 4.7 to 3.7 at Week 8 was observed (on a 7 point scale
where lower is better). Finally, the adverse event profile appeared
generally consistent with previous studies.
[0816] It is expected that deutetrabenazine, other deuterium
substituted tetrabenazines and valbenazine will be efficacious in
the treatment of Tourette syndrome and other movement disorders and
symptoms, such as tics, stereotypy, akathisia, dyskinesia, and
restless legs syndrome, and that the dosing regimens and methods
disclosed herein will yield significant patient benefits.
Twelve-Week Randomized Phase 2/3 Study of Safety and Efficacy in TS
Patients
[0817] Purpose.
[0818] The primary objective of this study is to evaluate the
efficacy of deutetrabenazine to reduce motor and phonic tics
associated with TS; the secondary objective of this study is to
evaluate the safety and tolerability of titration and maintenance
therapy with deutetrabenazine.
[0819] Study Design.
[0820] This is a Phase 2/3, randomized, double-blind,
placebo-controlled, parallel group study in which patients with
tics associated with TS will be invited to participate. The study
will include male and female patients between 6 and 16 years of age
(inclusive) with a tic associated with Tourette syndrome (TS).
Patients will be randomized and stratified by age at baseline [6 to
11 years, 12 to 16 years]). The dose of study drug for each patient
will be titrated to an optimal level followed by maintenance
therapy at that dose. The overall treatment period will be 12 weeks
in duration. The titration period will be 7 weeks, and the
maintenance period will be 5 weeks, which will be followed by a
washout period of 1 week. Patients
[0821] Inclusion Criteria.
[0822] Patients may be enrolled in the study if they meet all of
the following criteria: 6 to 16 years of age, inclusive, at
baseline; weight of at least 44 pounds (20 kg) at baseline; meets
the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V) diagnostic criteria for TS and, in the opinion of
the investigator, patient, and caregiver/adult, the patient's
active tics are causing distress or impairment; TTS of 20 or higher
on the YGTSS at screening and baseline; able to swallow study
medication whole; patient and caregiver/adult are willing to adhere
to the medication regimen and to comply with all study procedures;
good general health, as indicated by medical and psychiatric
history as well as physical and neurological examination; ability
to understand the nature of the study and its procedures, and
expected to complete the study as designed (in investigator's
opinion); written informed consent; women/girls of childbearing
potential (not surgically sterile (.gtoreq.3 months)--via tubal
ligation, hysterectomy, oophorectomy--or congenitally sterile)
whose male partners are of childbearing potential must use
contraception for the duration of the study and for 30 days after
discontinuation of study drug (acceptable methods of contraception
are those with a failure rate of less than 1% per year, e.g., IUD,
oral, implanted, transdermal, or injected hormonal contraceptive,
barrier method with spermicide, and partner vasectomy.
[0823] Exclusion Criteria.
[0824] Patients will not be enrolled in this study if they meet any
of the following criteria: neurologic disorder other than TS that
could obscure the evaluation of tics; patient's predominant
movement disorder is stereotypy (coordinated movements that repeat
continually and identically) associated with Autism Spectrum
Disorder; confirmed diagnosis of bipolar disorder, schizophrenia,
or another psychotic disorder; clinically significant depression at
screening or baseline (but patients receiving antidepressant
therapy may be enrolled if on a stable dose for at least 6 weeks
before screening (see list below for prohibited antidepressants);
history of suicidal intent or related behaviors within 2 years of
screening: previous intent to act on suicidal ideation with a
specific plan, irrespective of level of ambivalence, at the time of
suicidal thought; previous suicidal preparatory acts or behavior;
history of a previous actual, interrupted, or aborted suicide
attempt; a first-degree relative who has completed suicide;
clinically significant OCD at baseline that, in the opinion of the
investigator, is the primary cause of impairment; patient has
received CBIT for TS or CBT for OCD within 4 weeks of screening;
patient has received any of the following concomitant medications
for tics within the specified exclusionary windows of screening:
[0825] Within 3 months: depot neuroleptics, botulinum toxin, or
tetrabenazine; [0826] Within 21 days: reserpine; [0827] Within 14
days: monoamine oxidase inhibitors, neuroleptics (oral), typical
and atypical antipsychotics, metoclopramide, levodopa, and dopamine
agonists (note: use of benzodiazepines is allowed if primary use is
not for tics and dosing has been stable for at least 4 weeks before
screening; use of topiramate (up to 200 mg/day) is allowed if
dosing has been stable for at least 4 weeks before screening; and
use of guanfacine or clonidine is allowed if dosing has been stable
for at least 4 weeks before screening); treatment with deep brain
stimulation, or transmagnetic stimulation or transcranial direct
current stimulation for reduction of tics within 4 weeks of the
screening visit; an unstable or serious medical illness at
screening or baseline; patient requires treatment with drugs known
to prolong the QT interval (list below); QTcF interval value
>440 msec on 12-lead ECG at screening; evidence of hepatic
impairment (as indicated by AST or ALT >2.5.times.the upper
limit of the normal range (ULN) at screening or ALP or total
bilirubin (Tbil) >2.times.ULN at screening, though patients with
Gilbert's Syndrome and patients with abnormalities in 2 or more of
AST, ALT, ALP, and Tbil are eligible to participate if approved by
the medical monitor; evidence of clinically significant renal
impairment, indicated by a serum creatinine >1.5.times.ULN at
screening; known allergy to any of the components of the study drug
product; patient has participated in an investigational drug or
device trial and received study drug/intervention within 30 days or
5 drug half-lives of baseline, whichever is longer; pregnant or
breastfeeding; history of or acknowledged alcohol or substance
abuse in the previous 12 months, as defined in the DSM-V; positive
urine drug screen test result or is unable to refrain from
substance abuse throughout the study; and a DSM-V diagnosis based
on the MINI Kid Inventory modules performed at screening that, in
the opinion of the investigator, makes the patient unsuitable for
the study.
[0828] Prohibited drugs include: azithromycin,
chloroquine/Mefloquine, clarithromycina, domperidone, droperidol,
erythromycina, moxifloxacin, sevoflurane, probucol, sparfloxacin,
chlorpromazine, aripiprazole, haloperidol, asenapine maleate,
loxapine, clozapine, molindone, iloperidone, perphenazine,
lurasidone, pimozide, olanzapine, prochlorperazine,
olanzapine/fluoxetine, thioridazine paliperidone, thiothixene,
quetiapine, trifluoperazine, risperidone, promethazine-containing
compounds, ziprasidone, and tiapride.
[0829] Efficacy Endpoints.
[0830] The study's primary efficacy endpoint will be the change in
the Total Tic Score (TTS) of the Yale Global Tic Severity Scale
(YGTSS) from baseline to week 12, with a goal of reducing motor and
phonic/vocal tics. Secondary efficacy endpoints will be changes in
the Tourette Syndrome-Clinical Global Impression (TS-CGI) score,
Tourette Syndrome-Patient Global Impression of Severity (TS-PGIS)
score, and the Gilles de la Tourette Syndrome-Quality of Life
(GTS-QOL) physical/activities of daily living (ADL) subscale, all
from baseline to week 12.
[0831] Safety Endpoints.
[0832] Safety endpoints will be: incidence of adverse events;
observed values and changes from baseline in vital signs; observed
values and change from baseline in the Children's Depression
Inventory 2 (CDI-2; Parent and Self-report versions); observed
values in the children's Columbia Suicide Severity Rating Scale
(C-SSRS); observed values in electrocardiogram (ECG) parameters and
shifts from screening for clinically significant abnormal findings;
and observed values and changes from screening in clinical
laboratory parameters (hematology, chemistry, and urinalysis).
[0833] Titration Period (7 Weeks).
[0834] Patients who remain eligible for participation in the study
will be randomized at the baseline visit (day 1) and that evening
(ie, after the study visit) will receive 6 mg of blinded study drug
with food.
[0835] The dose of the study drug will be increased until 1) there
is optimal reduction of tics, as determined by the investigator, in
consultation with the patient and caregiver/adult; 2) the dose is
not tolerable.
[0836] Maintenance Period.
[0837] At the end of the titration period, the patient's dose will
be established for the maintenance period. Patients will continue
to receive their maintenance dose over the next 5 weeks, although
dose reductions for adverse events are allowed. Patients will
return to the clinic at weeks 9 and 12 for assessments of safety
and efficacy. At week 12, patients will undergo a complete
evaluation, including safety and efficacy measures.
[0838] Washout Period.
[0839] All patients will discontinue study drug at the week 12
visit and will return 1 week later for evaluation of safety and tic
reduction (week 13).
[0840] Dose Regimen.
[0841] As discussed above, study drug will be administered as oral
tablets at a starting dose of 6 mg once daily and titrated. Tablets
of deutetrabenazine will be available in the following dose
strengths: 6, 9, 12, 15, and 18 mg, distinguishable by imprint and
color. Instruction will be provided to ensure that: the starting
dose of 6 mg in all patients will be administered in the evening on
days 1 and 2, followed by AM administration for the remainder of
week 1 (if body weight is <40 kg); study drug should be
swallowed whole and taken with food; subsequent daily doses of 12
mg and higher will be administered twice daily in 2 divided doses,
approximately 8 to 10 hours apart during the day; a minimum of 6
hours should elapse between doses; if a patient misses a dose, and
it is within 6 hours of the next dose, the missed dose should be
skipped; if patients experience insomnia while taking the initial
6-mg dose in the evening, they may switch to taking it as a morning
dose for 2 days; after week 1, dose increases should not occur more
frequently than every 5 days; and dose reductions, if required,
should be in increments of 6 mg.
[0842] Blinding and Randomization.
[0843] Patients will be randomly assigned to receive treatment with
deutetrabenazine or matching placebo in a 1:1 ratio.
[0844] Expected Results.
[0845] It is expected that administration of a tolerable amount of
deutetrabenazine, between 6 and 48 mg, in the above study in
Tourette syndrome patients will: reduce total tic severity, both
motor and phonic/vocal tics, impairment, and/or global severity
scores, improve quality of life, overall life satisfaction, and/or
patient or clinical global impression of change, and improve
(lengthen) tic-free interval. It is expected that safety will be
consistent with what has been observed in previous studies.
Long-Term Open-Label Phase 3 Study of Safety and Efficacy in TS
Patients
[0846] Purpose.
[0847] The primary objective of this study is to evaluate the
safety and tolerability of long-term therapy with deutetrabenazine;
the secondary objective is to evaluate efficacy.
[0848] Study Design.
[0849] The study will include male and female patients with a tic
associated with Tourette syndrome (TS) who have previously
completed participation in either of the above clinical studies of
deutetrabenazine.
[0850] Screening.
[0851] Informed consent/assent will be obtained before any study
procedures are performed. Patients who have been off study drug for
several months at the time of enrollment, and who are stable from a
medical and psychiatric standpoint, will undergo a screening
evaluation as described above in the randomized study. To reduce
patient burden, some data collected in the randomized study above
will be used to provide corresponding data in this open label
study. Patients may be rescreened at the discretion of the medical
monitor. Inclusion and exclusion criteria will be similar to those
discussed above for the randomized trial, with the exception that
participation in either of the trials above is an inclusion, and
not an exclusion, criterion, and that data regarding disqualifying
DSM-V diagnoses may be obtained from the screening visit of the
randomized study.
[0852] Baseline Visit.
[0853] For patients enrolled in the randomized study above, the
baseline visit will occur simultaneously with the week 13 visit of
that study. Week 13 assessments specified for that are also
specified for the baseline visit of that study need not be
repeated. For all patients, the baseline visit will occur on the
same day as the scheduled first dose of the study drug (day 1). For
patients with clinically significant laboratory abnormalities at
week 12 in the randomized study above, the week 13 value will serve
as baseline in this study. Rollover for such patients must be
approved by the medical monitor and may be delayed.
[0854] Titration Period (7 Weeks).
[0855] As patients from the pilot study will have been off study
drug for several months at the time of enrollment, and since
patients from the randomized study will have discontinued study
drug or placebo for 1 week, all patients will undergo dose
titration in this study. Patients will receive 6 mg of
deutetrabenazine with food on the evening of day 1.
[0856] Maintenance Period (47 Weeks).
[0857] At the end of the titration period, the patient's initial
dose for the maintenance period will be established. Dose
adjustments of deutetrabenazine (upward or downward) may be made
during the maintenance period, if necessary, but not more often
than every 5 days and only in increments of 6 mg. Dose adjustments
should be made based on all available information, including the
patient and caregiver/adult reports of adverse events and tic
reduction, the clinical assessment of safety and efficacy by the
investigator, the patient's weight and CYP2D6 medication status,
and information from the rating scales. During the maintenance
period, in-person (in-clinic) study visits will be scheduled at
weeks 8, 15, 28, 41, and 54 for assessments of safety and efficacy.
At week 54, patients will undergo a complete evaluation as above in
the randomized trial.
[0858] Washout and Follow-Up.
[0859] All patients will discontinue study drug at the week 54
visit and will return 1 week later (week 55) for evaluation of
safety and tic reduction. Patients will have a follow-up telephone
contact for safety evaluation 1 week after the end of the washout
period (2 weeks after their last dose of study drug [week 56]).
[0860] Dose Regimen.
[0861] Study drug will be administered as above for the randomized
trial.
[0862] Study Endpoints.
[0863] Safety endpoints will be as above in the randomized study.
Efficacy endpoints will include the Primary and Secondary Efficacy
Endpoints as above in the randomized study, with a goal of reducing
severity of motor and phonic/vocal tics. Exploratory endpoints be
as above in the randomized study, from baseline to each visit.
[0864] Expected Results.
[0865] It is expected that administration of a tolerable amount of
deutetrabenazine, between 6 and 48 mg, in the above study in
Tourette syndrome patients will: reduce total tic severity, both
motor and phonic/vocal tics, impairment, and/or global severity
scores, improve quality of life, overall life satisfaction, and/or
patient global impression of severity or clinical global impression
of change, and improve (lengthen) tic-free interval. It is expected
that safety will be consistent with what has been observed in
previous studies.
QT Prolongation
[0866] Drug-drug interactions in the treatment of patients with HD
and other disorders involving abnormal involuntary movement may
also be a serious concern. Depression is a common comorbidity in HD
and patients are often treated with selective serotonin reuptake
inhibitors (SSRIs), including citalopram and escitalopram, that
have a risk for QT prolongation. Additionally, owing to frequent
behavioral abnormalities, several studies indicated that patients
with HD often receive treatment with antipsychotics (one-quarter up
to two-thirds of patients of HD have received antipsychotics.
Antipsychotics are known to prolong the QT interval. According to
FDA guidance, prolongation of the QT interval can favor the
development of cardiac arrhythmias, such as torsade de pointes,
which can degenerate into ventricular fibrillation and lead to
death. Per the United States prescribing information, tetrabenazine
should not be used in conjunction with agents known to prolong the
QT interval.
[0867] Study Design.
[0868] Given the known risk for tetrabenazine to increase the QT
interval, a TQT study of deutetrabenazine, which included
tetrabenazine as a treatment arm, was conducted in 48 healthy
volunteers. This was a single-center, randomized, double-blind,
placebo- and positive-controlled six-period crossover study to
evaluate the effects of low-dose (12 mg) and high-dose (24 mg)
deutetrabenazine on cardiac repolarization, based on
placebo-corrected, time-matched changes from baseline in the QTcF
interval. Assay sensitivity was established by using moxifloxacin
400 mg as the positive control.
[0869] The key outcome measure was to determine the effect of
single doses of deutetrabenazine on the QTc interval. A 50 mg dose
of tetrabenazine was selected as this was the maximal dose employed
in the TQT study for tetrabenazine and resulted in the Warning and
Precaution in the product label. A 24-mg dose of deutetrabenazine
was selected as it provides comparable systemic exposure (AUC) to
50 mg of tetrabenazine, but with a lower peak concentration
(Cmax).
[0870] Results.
[0871] For deutetrabenazine, 12-mg and 24-mg doses led to
placebo-corrected time-matched maximal increases in QTc of 2.8 ms
and 4.5 ms, respectively. For deutetrabenazine, the
placebo-corrected change from baseline in QTcF and the upper bound
of the two-sided 90% confidence interval was below the threshold of
regulatory concern (5 ms) for both dose levels. In contrast, the
maximum time-matched, placebo-adjusted change from baseline in QTcF
for tetrabenazine 50 mg was 7.6 ms, consistent with the
tetrabenazine prescribing information. Results are given below in
Table 25.
TABLE-US-00025 TABLE 25 Maximum Placebo-Adjusted Change from
Baseline in QTcF with deutetrabenazine and Tetrabenazine Tetra-
DTBZ DTBZ benazine Moxifloxacin Parameter 12 mg 24 mg 50 mg 400 mg
Placebo-Adjusted 2.8 4.5 7.6 14.0 Change from Baseline (ms) 90%
2-sided (0.7, 4.8) (2.4, 6.5) (5.6, 9.5) (11.9, 16.0) Confidence
Interval
[0872] In the table above, .DELTA..DELTA.QTcF is defined as the
difference between the least squares mean change from baseline for
the active drug and placebo. deutetrabenazine was compared with
deutetrabenazine placebo (administered under fed conditions) and
tetrabenazine was compared with tetrabenazine placebo (administered
under fasted conditions). The maximal .DELTA..DELTA.QTcF was
observed at the 8-hour time point for deutetrabenazine and the
3-hour time point for tetrabenazine. The upper limit of the 95%
one-sided confidence interval is the upper limit of the 90% 2-sided
confidence interval.
[0873] Conclusion.
[0874] These results support the fact that the differentiated
pharmacokinetic profile and lower C.sub.max associated with
deutetrabenazine compared with tetrabenazine improves the safety
profile of deutetrabenazine by reducing the risk for
life-threatening arrhythmias.
[0875] From the foregoing description, one skilled in the art can
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *