Note: Descriptions are shown in the official language in which they were submitted.
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USE OF REBOXETINE TO TREAT NERVOUS SYSTEM DISORDERS
Inventor: Herriot Tabuteau
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Pat. App. Serial No. 16/740,329,
filed January
10, 2020; U.S. Pat. App. Serial No. 16/740,409, filed January 11, 2020; U.S.
Pat. App. Serial No.
16/740,410, filed January 11, 2020; U.S. Pat. App. Serial No. 16/740,411,
filed January 11,
2020; U.S. Prov. Pat. App. No. 62/943,077, filed December 3, 2019; and U.S.
Prov. Pat. App.
No. 62/946,295, filed December 10, 2019; all of which are incorporated by
reference herein
in their entirety.
BACKGROUND
Narcolepsy is a serious and debilitating neurological condition that causes
dysregulation of the sleep-wake cycle and is characterized clinically by
excessive daytime
sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and
disrupted
nocturnal sleep. Narcolepsy is estimated to afflict an estimated 185,000
individuals in the U.S.
Cataplexy is seen in an estimated 70% of narcolepsy patients and is a sudden
reduction or loss
of muscle tone while a patient is awake, typically triggered by strong
emotions such as
laughter, fear, anger, stress, or excitement. Type 1 narcolepsy includes
cataplexy, while Type
2 narcolepsy does not include cataplexy. Narcolepsy interferes with cognitive,
psychological,
and social functioning, increases the risk of work- and driving-related
accidents, and is
associated with a 1.5 fold higher mortality rate. Depression is reported in up
to 57% of
patients. Unfortunately, currently approved treatments are few for this under-
diagnosed
orphan condition and are limited by variability in efficacy from patient to
patient, tolerability
issues and the need for Drug Enforcement Administration (DEA) scheduling.
SUMMARY
Described herein are methods of treating a nervous system disorder, comprising
administering an antidepressant, such as a selective norepinephrine inhibitor,
e.g.
atonnoxetine, edivoxetine, reboxetine, or 5,5-reboxetine to a human being in
need thereof.
Described herein are methods of treating narcolepsy with cataplexy, comprising
administering an antidepressant, such as a selective norepinephrine inhibitor,
e.g.
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atonnoxetine, edivoxetine, or reboxetine (including S,S-reboxetine), to a
human being in need
thereof.
Some embodiments include use of an antidepressant, such as a selective
norepinephrine inhibitor, e.g. atonnoxetine, edivoxetine, or reboxetine
(including S,S-
reboxetine), in the manufacture of a medicament for the treatment of
narcolepsy with
cataplexy.
Some embodiments include a kit comprising a pharmaceutical composition
comprising an antidepressant, such as a selective norepinephrine inhibitor,
e.g. atonnoxetine,
edivoxetine, or reboxetine (including 5,5-reboxetine), and instructions to use
the
pharmaceutical composition to treat narcolepsy with cataplexy in a human
being.
In some embodiments, an antidepressant, such as a selective norepinephrine
inhibitor, e.g. atonnoxetine, edivoxetine, or reboxetine (including 5,5-
reboxetine), is
administered at least once daily for more than two weeks. In some embodiments,
the human
being experiences a reduction in the number of cataplexy attacks in a week, a
reduction in
the Epworth Sleepiness Scale (ESS) score, a reduction in the Maintenance of
Wakefulness Test
(MWT) score, a reduction in the Narcolepsy Symptom Assessment Score (NSAQ), a
reduction
in the Patient Global Impression of Severity (PGI-S) score, a score below 4 in
the Patient Global
Impression of Change (PGI-C), or a reduction in the Hamilton Depression Rating
Scale (HAM-
D), or improvement in the ability to concentrate (e.g. on the NSAQ) as a
result of the
treatment.
Some embodiments include a method of rapidly reducing the number of cataplexy
attacks in a human being having narcolepsy with cataplexy, comprising
administering about
8 mg to about 10 mg of reboxetine daily for at least two weeks to a human
being in need
thereof, wherein one week after the start of the treatment, the human being
has at least 30%
fewer cataplexy attacks as compared to baseline and the reduction in the
number of cataplexy
attacks is statistically significant as compared to administering a placebo
with p<0.01. In some
embodiments, the reduction in the number of cataplexy attacks is statistically
significant as
compared to administering a placebo with p<0.001.
Some embodiments include a method of improving the ability to concentrate
comprising administering an antidepressant, such as a selective norepinephrine
inhibitor, e.g.
atonnoxetine, edivoxetine, or reboxetine (including 5,5-reboxetine), to a
mammal or a human
being in need thereof.
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Some embodiments include a method of improving the ability to concentrate in a
human being having narcolepsy with cataplexy, comprising administering about 8
mg to about
mg of reboxetine daily for at least two weeks to a human being in need
thereof, wherein,
prior to the start of treatment, the human being has an ability to concentrate
that is
5
"average," "poor," or "very poor," and two weeks after the start of the
treatment, the human
being has an ability to concentrate that is "good" or "very good," as
determined by the Ability
to Concentrate Item of the Narcolepsy Symptom Assessment Questionnaire. In
some
embodiments, the reboxetine is racennic reboxetine. In some embodiments, the
reboxetine
is esreboxetine.
10 Some
embodiments include a method of reducing the number of inadvertent naps in
a human being having narcolepsy with cataplexy, comprising administering about
8 mg to
about 10 mg of reboxetine daily for at least two weeks to a human being in
need thereof,
wherein two weeks after the start of the treatment, the human being has at
least 20% fewer
inadvertent naps per week as compared to the week before the patient first
receives
reboxetine. In some embodiments, the reboxetine is racennic reboxetine. In
some
embodiments, the reboxetine is esreboxetine.
Some embodiments include a method of improving sleep quality in a human being
having narcolepsy with cataplexy, comprising administering about 8 mg to about
10 mg of
reboxetine daily for at least two weeks to a human being in need thereof,
wherein two weeks
after the start of the treatment, the human being reports having improved
sleep quality as
compared to the week before the patient first receives reboxetine. In some
embodiments,
the reboxetine is racennic reboxetine. In some embodiments, the reboxetine is
esreboxetine.
Some embodiments include a method of reducing night awakenings in a human
being
having narcolepsy with cataplexy, comprising administering about 8 mg to about
10 mg of
reboxetine daily for at least two weeks to a human being in need thereof,
wherein two weeks
after the start of the treatment, the human being reports having fewer night
awakenings as
compared to the week before the patient first receives reboxetine. In some
embodiments,
the reboxetine is racennic reboxetine. In some embodiments, the reboxetine is
esreboxetine.
Some embodiments include a method of reducing sleep paralysis in a human being
having narcolepsy with cataplexy, comprising administering about 8 mg to about
10 mg of
reboxetine daily for at least two weeks to a human being in need thereof,
wherein two weeks
after the start of the treatment, the human being reports having fewer sleep
paralysis
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episodes as compared to the week before the patient first receives reboxetine.
In some
embodiments, the reboxetine is racennic reboxetine. In some embodiments, the
reboxetine
is esreboxetine.
Some embodiments include a method of reducing hypnagogic hallucinations in a
human being having narcolepsy with cataplexy, comprising administering about 8
mg to about
mg of reboxetine daily for at least two weeks to a human being in need
thereof, wherein
two weeks after the start of the treatment, the human being reports having
fewer hypnagogic
hallucinations as compared to the week before the patient first receives
reboxetine. In some
embodiments, the reboxetine is racennic reboxetine. In some embodiments, the
reboxetine
10 is esreboxetine.
Some embodiments include a method of improving the ability to concentrate in a
human being suffering from narcolepsy, comprising administering reboxetine to
a human
being in need thereof. In some embodiments, the reboxetine is racennic
reboxetine. In some
embodiments, the reboxetine is esreboxetine.
Some embodiments include a method of treating narcolepsy with cataplexy,
comprising
administering reboxetine to a human being in need thereof, wherein reboxetine
is
administered at least once daily for more than two weeks, wherein, two weeks
after the
beginning of treatment, the human being experiences a reduction in the number
of cataplexy
attacks in a week, a reduction in the Epworth Sleepiness Scale score, a
decrease in the
cataplexy subscore on the Ullanlinna Narcolepsy Scale (NUS), or a reduction in
the
Maintenance of Wakefulness Test score as a result of the treatment.
Some embodiments include use of reboxetine in the manufacture of a medicament
for
the treatment of narcolepsy with cataplexy, wherein reboxetine is administered
at least once
daily for at least three weeks. In some embodiments, the reboxetine is
racennic reboxetine.
In some embodiments, the reboxetine is esreboxetine.
Some embodiments include a kit comprising a pharmaceutical composition
comprising
reboxetine and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being, wherein reboxetine is administered at least once
daily for at least
three weeks. In some embodiments, the reboxetine is racennic reboxetine. In
some
.. embodiments, the reboxetine is esreboxetine.
Some embodiments include a method of treating fibronnyalgia, comprising
administering esreboxetine to a human being in need thereof, wherein a daily
dose of about
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1 mg to about 2 mg of esreboxetine is administered for at least six weeks,
wherein the human
being experiences a reduction in fibronnyalgia pain during the course of the
treatment, as
measured by a visual analog scale (VAS) score, that is greater than the
reduction in pain that
the human being would have experienced by administering a placebo.
Some embodiments include a method of treating fibronnyalgia, comprising
administering esreboxetine to a human being in need thereof, wherein a daily
dose of about
2 mg to about 4 mg of esreboxetine is administered for at least six weeks,
wherein the human
being experiences a reduction in pain during the course of the treatment, as
measured by a
visual analog scale (VAS) score, that is greater than the reduction in pain
that the human being
.. would have experienced by administering a placebo.
Some embodiments include a method of treating fibronnyalgia, comprising
administering esreboxetine to a human being in need thereof, wherein a daily
dose of about
0.5 mg to about 1 mg of esreboxetine is administered for at least six weeks,
wherein the
human being experiences a reduction in pain during the course of the
treatment, as measured
by a visual analog scale (VAS) score, that is greater than the reduction in
pain that the human
being would have experienced by administering a placebo.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts the change in weekly cataplexy attacks for human patients who
received
reboxetine and placebo as described in Example 22.
FIG. 2 depicts the number of human patients with a 50% or greater reduction in
weekly
cataplexy attacks, where the human patients received reboxetine or placebo as
described in
Example 22.
FIG. 3 depicts the number of human patients with a 75% or greater reduction in
weekly
cataplexy attacks, where the human patients received reboxetine or placebo as
described in
Example 22.
FIG. 4 depicts the change in Epworth Sleepiness Scale Score for human patients
who
received reboxetine and placebo as described in Example 22.
FIG. 5 depicts the reduction in the weekly frequency of inadvertent naps for
human
patients who received reboxetine and placebo as described in Example 22.
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FIG. 6 depicts the number of human patients with a 50% or greater reduction
inadvertent naps, where the human patients received reboxetine or placebo as
described in
Example 22.
FIG. 7 depicts the improvement in the ability to concentrate score for human
patients
who received reboxetine and placebo as described in Example 22.
FIG. 8 depicts the number of human patients with a "very good" or "good"
ability to
concentrate, where the human patients received reboxetine or placebo as
described in
Example 22.
FIG. 9 depicts the proportion of human patients demonstrating improvement in
sleep
quality, night awakenings, sleep paralysis episodes, and hynagogic
hallucinations.
DETAILED DESCRIPTION
An antidepressant, such as reboxetine or S,S-reboxetine, may be used to treat
a
condition such as a nervous system disorder, including an addictive disorder
(including those
due to alcohol, nicotine, and other psychoactive substances), a withdrawal
syndrome, an
adjustment disorder (including depressed mood, anxiety, mixed anxiety and
depressed mood,
disturbance of conduct, and mixed disturbance of conduct and mood), depression
(including
major depressive disorder, alone or in combination with other
antidepressants), an age-
associated learning or mental disorder (including Alzheimer's disease),
anorexia nervosa
apathy, an attention-deficit (or another cognitive) disorder due to general
medical conditions,
attention-deficit hyperactivity disorder (ADHD), bipolar disorder, bulimia
nervosa, chronic
fatigue syndrome, chronic or acute stress, chronic pain, conduct disorder,
cyclothynnic
disorder, depression (including adolescent depression and minor depression),
dysthynnic
disorder, fibronnyalgia and other sonnatofornn disorders (including
sonnatization disorder,
conversion disorder, pain disorder, hypochondriaisnn, body dysnnorphic
disorder,
undifferentiated sonnatofornn disorder, and sonnatofornn NOS), generalized
anxiety disorder
(GAD), incontinence (i.e., stress incontinence, genuine stress incontinence,
and mixed
incontinence), stress urinary incontinence, an inhalation disorder, an
intoxication disorders
(alcohol addiction), mania, migraine headaches, obesity (e.g., reducing the
weight of obese
or overweight patients), an obsessive compulsive disorder or a related
spectrum disorder,
oppositional defiant disorder, panic disorder, peripheral neuropathy, post-
traumatic stress
disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and
late luteal phase
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dysphoric disorder), a psychotic disorder (including schizophrenia, negative
symptoms of
schizophrenia, schizoaffective or schizophrenifornn disorder, either alone or
as an adjuvant
therapy), seasonal affective disorder, a sleep disorder (such as narcolepsy or
enuresis), social
phobia (including social anxiety disorder), a specific developmental disorder,
selective
serotonin reuptake inhibition (SSRI) "poop out" syndrome (i.e., wherein a
patient who fails to
maintain a satisfactory response to SSRI therapy after an initial period of
satisfactory
response), TIC disorders (e.g., Tourette's Disease), post-shingles pain,
painful diabetic
peripheral neuropathy, postherpetic neuralgia, syncope, and/or vasovagal
syncope, etc. In
some embodiments, S,S-reboxetine is used to treat fibronnyalgia. In some
embodiments,
reboxetine is used to treat fibronnyalgia.
Treatment with reboxetine (including S,S-reboxetine), may result in
improvement of
the symptoms of a disease. For example, for pain conditions such as
fibronnyalgia, the patient
may experience a reduction in pain measured on a visual analog scale (VAS),
such as 0-100
mm, which is greater than what would be experienced by administering a
placebo. In some
embodiments, the improvement in VAS score be at least about 10%, at least
about 20%, at
least about 30%, at least about 40%, at least about 50%, at least about 60%,
at least about
70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-
20%, about
20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%,
about
80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-
100%, e.g.
at least about 50 mm, at least about 40 mm, at least about 30 mm, at least
about 20 mm, at
least about 10 mm, about 0-10 mm, about 10-20 mm, about 20-30 mm, about 30-40
mm,
about 40-50 mm, about 0-25 mm, or about 25-50 mm more than would be
experienced by
administering a placebo. In some embodiments, the improvement in VAS score be
at least
about 10%, at least about 20%, at least about 30%, at least about 40%, at
least about 50%, at
least about 60%, at least about 70%, at least about 80%, at least about 90%,
about 1-5%,
about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-
60%,
about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-
50%,
about 50-75%, or about 75-100%, e.g. at least about 50 mm, at least about 40
mm, at least
about 30 mm, at least about 20 mm, at least about 10 mm, about 0-10 mm, about
10-20 mm,
about 20-30 mm, about 30-40 mm, about 40-50 mm, about 0-25 mm, or about 25-50
mm as
compared to baseline (e.g. right before treatment starts).
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An antidepressant, such as bupropion, hydroxybupropion,
erythrohydroxybupropion,
threohydroxybupropion, clonniprannine, doxepin, fluoxetine, nnianserin,
inniprannine, 2-
chloroinniprannine, annitriptyline, annoxapine, desiprannine, protriptyline,
trinniprannine,
nortriptyline, nnaprotiline, phenelzine, isocarboxazid, tranylcypronnine,
paroxetine,
trazodone, citaloprann, sertraline, aryloxy indanannine, benactyzine,
escitaloprann,
fluvoxannine, venlafaxine, desvenlafaxine, duloxetine, nnirtazapine,
nefazodone, selegiline,
sibutrannine, nnilnacipran, tesofensine, brasofensine, nnoclobennide,
rasagiline, nialannide,
iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin,
iprindole,
lofeprannine, opiprannol, norfluoxetine, dapoxetine, ketannine, etc.,
including a
norepinephrine reuptake inhibitor such as atonnoxetine, edivoxetine, or
reboxetine (including
S,S-reboxetine), have the potential to treat the symptoms of narcolepsy.
Many antidepressants, such as norepinephrine reuptake inhibitors, e.g.
atonnoxetine,
edivoxetine, or reboxetine (including S,S-reboxetine), lack of DEA scheduling,
which would
represent a significant benefit to patients living with this condition.
A person may have Type 1 narcolepsy if Criteria A and B are met:
A. The patient has daily periods of irrepressible need to sleep or daytime
lapses
into sleep occurring for at least 3 months
B. The presence of one or both of the following:
1. Cataplexy (as defined under Essential Features) and a mean sleep
latency of <8 minutes and Sleep-Onset REM
Periods (SOREMPs) on a Mean
Sleep Latency Test (MSLT) performed according to standard techniques. A
SOREMP (within 15 minutes of sleep onset) on the preceding laboratory-based
polysonnnography (PSG) may replace one of the SOREMPs on the MSLT
2. CSF hypocretin-1 concentrations measured by innnnunoreactivity
either <110 pg/nnL or <1/3 of mean values obtained in normal subjects with the
same assay
In young children, narcolepsy may sometimes present as excessively long night
sleep
or by resumption of previously discontinued daytime napping. If narcolepsy
Type 1 is strongly
suspected clinically but criteria B2 are not met, a possible strategy is to
repeat the MSLT
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having,
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daily periods of irrepressible need to sleep or daytime lapses into sleep
occurring for at least
about 3 months, at least 4 months, at least about 5 months, at least about 6
months, at least
about 7 months, at least about 8 months, at least about 9 months, at least
about 10 months,
at least about 11 months, at least about 12 months, at least about 13 months,
at least about
14 months, at least about 15 months, at least about 16 months, at least about
17 months, at
least about 18 months, at least about 2 years, at least about 3 years, at
least about 4 years,
at least about 5 years, at least about 10 years, at least about 15 years, at
least about 20 years,
at least about 25 years, at least about 30 years, at least about 40 years, at
least about 50
years, at least about 60 years, about 3-9 months, about 9-18 months, about 18
months to
about 2 years, about 2-5 years, about 5-10 years, about 10-15 years, about 15-
20 years, about
20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-
50 years,
about 50-60 years, or more.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having, a
.. mean sleep latency of less than about 1 minute, less than about 2 minutes,
less than about
3 minutes, less than about 4 minutes, less than about 5 minutes, less than
about 6 minutes,
less than about 7 minutes, less than about 8 minutes, about 0.1-1 minutes,
about 1-2 minutes,
about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes,
about 6-7
minutes, about 7-8 minutes, about 1 minute, about 2 minutes, about 3 minutes,
about 4
minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8
minutes.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having,
at least 2, at least 3, or at least 4 SOREMPs on an MSLT (Mean Sleep Latency
Test) performed
according to standard techniques. A SOREMP within 15 minutes of sleep onset on
the
preceding nocturnal PSG may replace one of the SOREMPs on the MSLT
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having,
CSF hypocretin-1 concentrations measured by innnnunoreactivity that are less
than about 40
pg/nnL, less than about 50 pg/nnL, less than about 60 pg/nnL, less than about
70 pg/nnL, less
than about 80 pg/nnL, less than about 90 pg/nnL, less than about 100 pg/nnL,
less than about
110 pg/nn L.
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Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having,
CSF hypocretin-1 concentrations measured by innnnunoreactivity that are less
than about
1/10, less than about 1/9, less than about 1/8, less than about 1/7, less than
about 1/6, less
than about 1/5, less than about 1/4, or less than about 1/3 of mean values
obtained in normal
subjects with the same assay.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may be, and/or may be selected
for being,
young children presenting with excessively long night sleep.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may be, and/or may be selected
for being,
young children presenting with resumption of previously discontinued daytime
napping.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having, a
diagnosis of narcolepsy with cataplexy that meets the International
Classification of Sleep
Disorders, Third Edition (ICSD-3) criteria.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having, a
cataplexy subscore on the Ullanlinna Narcolepsy Score (UNS) that is at least
1, at least about
2, at least about 3, at least about 4, at least about 5, at least about 6, at
least about 7, at least
about 8, at least about 9, at least about 10, about 11, about 1-2, about 2-3,
about 3-4, about
4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11,
about 2-4, about 4-
6, about 6-8, about 8-10, about 2-6, or about 6-10, or any number between 1
and 11.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having, a
score on the Epworth Sleepiness Scale (ESS) that is at least about 10, greater
than about 10,
at least about 11, at least about 12, at least about 13, at least about 14, at
least about 15, at
least about 16, at least about 17, at least about 18, at least about 19, at
least about 20, at
least about 21, at least about 22, at least about 23, at least about 24, about
10-11, about 11-
12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-
18, about 18-
19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 10-
13, about 13-
16, about 16-19, about 19-22, or about 22-24.
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Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having,
at least about 7, at least about 8, at least about 9, at least about 10, at
least about 11, at least
about 12, at least about 13, at least about 14, at least about 15, at least
about 16, at least
about 17, at least about 18, at least about 19, at least about 20, at least
about 21, at least
about 28, at least about 35, about 7-14, about 14-21, about 21-28, about 28-
35, about 35-49,
or about 49-70 cataplexy attacks per week.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) may have, and/or may be selected
for having, a
Maintenance of Wakefulness Test (MWT) score that is less than about 1 minutes,
less than
about 2 minutes, less than about 3 minutes, less than about 4 minutes, less
than about 5
minutes, less than about 6 minutes, less than about 7 minutes, less than about
8 minutes, less
than about 9 minutes, less than about 10 minutes, less than about 11 minutes,
less than about
12 minutes, less than about 13 minutes, less than about 14 minutes, less than
about 15
minutes, less than about 16 minutes, less than about 17 minutes, less than
about 18 minutes,
less than about 19 minutes, less than about 20 minutes, about 0-1 minutes,
about 1-2
minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6
minutes, about
6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about
10-11
minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about
14-15
minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about
18-19
minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12
minutes,
about 12-16 minutes, about 16-20, or about 0-19 minutes.
In some embodiments, the patient has had, and/or may be selected for having
had,
symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15
years, about 15-
20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40
years, about
40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-
65 years,
about 65-70 years, about 70-75, or more than 75 years prior to receiving an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
treatment.
In some embodiments, the patient has, and/or may be selected for having, an
age of
about 0-18 years, about 18-100 years, about 0-5 years, about 5-10 years, about
10-15 years,
about 15-18 years, about 18-20 years, about 15-20 years, about 18-25 years,
about 20-25
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years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-45
years, about 45-
50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70
years, about
70-75, or more than 75 years prior to receiving an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) for treatment.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may be, and/or may be selected for being female. In some embodiments, the
patient may be
selected for being female, nonlactating and nonpregnant.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may be, and/or may be selected for being male.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, any concomitant sleep
disorder. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, any concomitant sleep disorder
other than mild
sleep apnea (<15 events per hour) or mild to moderate sleep apnea (<30 events
per hour)
with stable treatment. Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, any clinically
significant conditions potentially causing EDS. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, any clinically significant psychiatric disorders. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, any type of depression that was not caused by
narcolepsy. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, any sleepiness caused by
depression that was
not caused by narcolepsy. Some patients treated with an antidepressant,
including a
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norepinephrine inhibitor such as reboxetine (including S,S-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an affective
disorder. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a psychiatric disorder.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a cerebral function disorder. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a movement disorder. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a dementia.
Some patients treated with an antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a motor
neuron disease.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not be concurrently taking sodium oxybate. Some patients treated with
an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not be
concurrently taking a
stimulant. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not be concurrently taking an anticonvulsant. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not be
concurrently taking
clonidine. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not be concurrently taking a selective serotonin reuptake inhibitor
(SSRI). Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not be
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concurrently taking a serotonin and norepinephrine re-uptake inhibitor (SNRI).
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not be
concurrently taking a nnonoannine oxidase inhibitor (MA01). Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not be
concurrently taking a
tricyclic antidepressant (TCA). Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not be concurrently taking a hypnotic. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not be
concurrently taking
an anxiolytic. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not be concurrently taking a sedating antihistamine. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not be
concurrently taking
an antipsychotic. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not be concurrently taking any other medication for the
treatment of
.. narcolepsy or cataplexy.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a neurodegenerative
disease. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a seizure disorder. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a convulsive disorder. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a diagnosis of cancer (except possibly basal cell carcinoma) within
the last 5 years.
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Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a bilirubin level more
than 2 times the
upper limit of normal. Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an alanine
anninotransferase level more than 2 times the upper limit of normal. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an aspartate anninotransferase level more than 2
times the upper
limit of normal. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, an alkaline
phosphatase
level more than 2 times the upper limit of normal.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having clinically significant
hypertension. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having uncontrolled hypertension. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having a history of cardiovascular disease.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having myocardial infarction. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having angina. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not having
disrhythnnias. Some patients treated with an antidepressant, including a
norepinephrine
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inhibitor such as reboxetine (including S,S-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having cardiac
failure.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having a history of narrow angle
glaucoma.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having gastric bypass. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having any condition that would be expected to affect drug
absorption.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, headaches. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a depression. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, major depression. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a treatment
resistant depression.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, treatment resistant
bipolar depression.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a bipolar disorder. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, cyclothynnia. Some patients treated with an
antidepressant, including
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a norepinephrine inhibitor such as reboxetine (including S,S-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a seasonal
affective disorder. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, a mood
disorder. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, chronic depression (e.g.
dysthynnia). Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a psychotic depression. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having a history of psychotic episodes. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having significant risk of self-injury, suicide, or
aggression towards others.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a postpartum depression.
Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a premenstrual dysphoric disorder
(PMDD).
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a situational depression. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an atypical depression. Some patients treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a mania. Some patients treated with an
antidepressant, including a
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norepinephrine inhibitor such as reboxetine (including S,S-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an anxiety
disorder. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, attention deficit
disorder (ADD).
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, attention deficit
disorder with
hyperactivity (ADDH). Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, attention
deficit/hyperactivity disorder (AD/HD). Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a manic condition. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an
obsessive-compulsive disorder. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a bulimia.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, obesity or weight-gain. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a chronic fatigue syndrome.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a premenstrual syndrome.
Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a substance addiction or abuse.
Some patients
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treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including S,S-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a nicotine addiction. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a psycho-sexual dysfunction. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a pseudobulbar affect. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, emotional lability.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, an anxiety disorder. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a phobia. Some patients treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a generalized anxiety disorder. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a social anxiety disorder.
Some patients treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a panic disorder. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an agoraphobia. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an
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obsessive-compulsive disorder. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, post-
traumatic stress disorder (PTSD). Some patients treated with an
antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a mania.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a manic depressive
illness. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a hyponnania. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a unipolar depression. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a stress disorder. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
sonnatofornn disorder. Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
personality disorder. Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a psychosis.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, schizophrenia. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a delusional disorder. Some patients treated with an
antidepressant,
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including a norepinephrine inhibitor such as reboxetine (including S,S-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a schizoaffective disorder. Some patients treated with an
antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
schizotypy. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, aggression.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, aggression in Alzheimer's disease. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, agitation. Some patients treated with
an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, agitation in Alzheimer's disease.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a drug dependence. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, addiction to cocaine. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, addiction to or dependence on a psychostinnulant.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, addiction to or dependence on crack.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, addiction to or dependence on cocaine.
Some patients
21
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treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including S,S-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, addiction to or dependence on speed.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, addiction to or dependence on
nnethannphetannine.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, addiction to or dependence on
nicotine.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, addiction to or
dependence on alcohol.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, addiction to or dependence on an
opioid. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, addiction to or dependence on an
anxiolytic
and/or a hypnotic drug. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, addiction
to or dependence on a cannabis (marijuana). Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, addiction to or dependence on an amphetamine. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, addiction to or dependence on a hallucinogen. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an addiction to or dependence on phencyclidine.
22
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Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, addiction to or
dependence on a volatile
solvent. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, addiction to or
dependence on a volatile
nitrite. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, senile dementia. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an Alzheimer's type dementia. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, memory loss. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an annnesia/annnestic syndrome. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an apilepsy. Some patients treated with an antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having,
disturbances of consciousness.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a coma. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a lowering of attention. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
23
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selected for not having, a speech disorder. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a voice spasm.
Some patients treated with an antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, Parkinson's
disease. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a Lennox-Gastaut
syndrome.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, autism. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a hyperkinetic syndrome. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, schizophrenia. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, had a stroke.
Some patients treated with an antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a cerebral
infarction. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, a cerebral
bleeding. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a cerebral arteriosclerosis. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a cerebral venous thrombosis. Some
patients treated
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with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a head injury.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, an akinesia. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an athetosis. Some patients treated with an
antidepressant, including
a norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an ataxia.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a ballisnnus. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a henniballisnnus. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a bradykinesia. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a cerebral
palsy.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
.. such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a chorea. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, Huntington's disease. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a rheumatic chorea. Some patients treated with an antidepressant,
including a
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norepinephrine inhibitor such as reboxetine (including S,S-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
Sydenhann's chorea.
Some patients treated with an antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a dyskinesia.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a tardive dyskinesia. Some
patients treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a dystonia. Some patients treated with an
antidepressant, including
a norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
blepharospasnn.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a spasmodic torticollis.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a dopamine-responsive dystonia. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, restless legs syndrome (RLS). Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a tremor. Some patients treated with an
antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an essential
tremor. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, burette's syndrome. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
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(including S,S-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, Wilson's disease.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a vascular dementia. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a dementia with Lewy bodies. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a mixed dementia. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a fronto-temporal dementia. Some patients treated with an
antidepressant, including
a norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, Creutzfeldt-
Jakob disease. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, a normal
pressure
hydrocephalus. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, Wernicke-
Korsakoff
Syndrome.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, Pick's disease. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a progressive bulbar palsy. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a primary lateral sclerosis (PLS). Some patients
treated with an
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antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a progressive muscular atrophy. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a post-polio syndrome (PPS). Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a spinal muscular atrophy (SMA).
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a spinal motor atrophy.
Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, Tay-Sach's disease. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a Sandoff disease. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a hereditary spastic paraplegia. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, Alzheimer's disease. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a prion-
related disease. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, a cerebellar
ataxia. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a spinocerebellar ataxia (SCA).
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Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a spinal muscular atrophy
(SMA). Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a bulbar muscular atrophy. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a Friedrich's ataxia. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, Lewy body disease. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, annyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, multiple sclerosis (MS). Some patients treated with
an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a multiple system atrophy.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, Shy-Drager syndrome. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a corticobasal degeneration. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a progressive supranuclear palsy.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
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may not have, and/or may be selected for not having, Wilson's disease. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, Menkes disease. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an adrenoleukodystrophy. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a cerebral
.. autosonnal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy
(CADASIL). Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, a muscular
dystrophy.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, a Charcot-Marie-Tooth
disease (CMT).
Some patients treated with an antidepressant, including a norepinephrine
inhibitor such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, a familial spastic paraparesis.
Some patients
.. treated with an antidepressant, including a norepinephrine inhibitor such
as reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a neurofibronnatosis. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
.. selected for not having, an olivopontine cerebellar atrophy or
degeneration. Some patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, a striatonigral degeneration. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, Guillain-Barr-syndrome.
Some patients treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
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reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a spastic paraplesia. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, epileptic seizures. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, nonepileptic
seizures. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, epilepsy. Some patients
treated with
an antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, febrile seizures. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, partial seizures. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, simple
partial seizures. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, Jacksonian
seizures. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, complex partial seizures. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an epilepsia partialis continua. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, generalized seizures. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
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having, generalized tonic-clonic seizures. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an absence seizure.
Some patients treated with an antidepressant, including a norepinephrine
inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, atonic seizures. Some
patients treated
with an antidepressant, including a norepinephrine inhibitor such as
reboxetine (including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, nnyoclonic seizures. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, juvenile nnyoclonic seizures. Some patients treated with an
antidepressant, including
a norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, infantile
spasm. Some patients treated with an antidepressant, including a
norepinephrine inhibitor
such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g. with
cataplexy and/or EDS)
may not have, and/or may be selected for not having, status epilepticus. Some
patients
treated with an antidepressant, including a norepinephrine inhibitor such as
reboxetine
(including 5,5-reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may
not have,
and/or may be selected for not having, Rett Syndrome. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a tinnitus. Some patients treated with an
antidepressant, including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having,
disturbances of consciousness disorders. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a sexual dysfunction. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a voice
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disorder due to uncontrolled laryngeal muscle spasms. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an abductor spasmodic dysphonia. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, an adductor spasmodic dysphonia. Some patients
treated with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a muscular tension dysphonia. Some patients treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a vocal tremor. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a diabetic neuropathy. Some patients treated with an antidepressant,
including a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
chemotherapy-induced neurotoxicity. Some patients treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, nnethotrexate neurotoxicity. Some patients treated with an
antidepressant, including
a norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a stress
urinary incontinence. Some patients treated with an antidepressant, including
a
norepinephrine inhibitor such as reboxetine (including 5,5-reboxetine) for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, urge urinary
incontinence. Some patients treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) for narcolepsy (e.g.
with cataplexy
and/or EDS) may not have, and/or may be selected for not having, fecal
incontinence. Some
patients treated with an antidepressant, including a norepinephrine inhibitor
such as
33
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reboxetine (including S,S-reboxetine) for narcolepsy (e.g. with cataplexy
and/or EDS) may not
have, and/or may be selected for not having, erectile dysfunction.
Cataplexy includes a sudden reduction or loss of muscle tone while a patient
is awake,
which may affect specific parts of the body or the entire body, such as
eyelids, head drop,
facial sagging and/or twitching, slurred speech, jaw weakness, weakness in
arms, shoulders,
or hands, and/or buckling of knees. Cataplexy may be pathognonnonic for
narcolepsy.
Cataplexy may be triggered by strong emotions, such as laughter, elation,
surprise, or anger.
Cataplexy may be partial or localized (in about 75% of cases) and is usually
of short duration.
The frequency of cataplexy may vary widely. Narcolepsy with cataplexy may be
socially
disabling and isolating.
Some patients being treated with an antidepressant, including a norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) may have, and/or may
be selected for
having, narcolepsy with cataplexy (Type 1) that is an autoinnnnune disorder
resulting in a loss
of hypocretin (orexin)-producing neurons in the CNS. Hypocretins (orexins) are
hypothalamic-
specific peptides with neuroexcitatory activity. A patient being treated
with an
antidepressant, including a norepinephrine inhibitor such as reboxetine
(including S,S-
reboxetine) for narcolepsy with cataplexy is, and may be selected for being, a
predisposed
individual with specific genetic markers including human leukocyte antigen
(HLA DQB1/06:02)
and/or T-cell receptor alpha variants. Some patients being treated with an
antidepressant,
including a norepinephrine inhibitor such as reboxetine (including 5,5-
reboxetine) may not
have, and may be selected for not having, narcolepsy associated with loss of
hypocretin
neurons. Some patients being treated with an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) may have, or may be
selected for
having, narcolepsy precipitated by seasonal Streptococcus infections, H1N1
influenza, and/or
H1N1 vaccination in genetically predisposed individuals.
Existing treatments for narcolepsy only address some of its symptoms, provide
variable efficacy, and have significant side effects. Additionally, all
existing treatments are
controlled substances.
According to the FDA, "there is a continued need for additional effective and
tolerable
treatment options for patients to improve their daily functioning." (The Voice
of the Patient,
A series of reports from the U.S. Food and Drug Administration's (FDA's)
Patient-Focused Drug
Development Initiative, Narcolepsy, June 2014. p. 25)
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In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce daytime
sleepiness by at
least about 1%, at least about 5%, at least about 10%, at least about 20%, at
least about 30%,
at least about 40%, at least about 50%, at least about 60%, at least about
70%, at least about
80%, at least about 90%, about 1-5%, about 5-10%, about 10-20%, about 20-30%,
about 30-
40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,
about 90-
100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as
compared to
baseline, placebo, or some other appropriate control (including an active
control, such as a
stimulant (e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil,
sodium oxybate,
a tricyclic antidepressant, a selective serotonin reuptake inhibitor (SSRI),
or a selective
norepinephrine reuptake inhibitor (SNRI)). This improvement may be observed at
e.g. 1
week, 2 weeks, overall, or at any other relevant time, such as 1 month, 6
months, 1 year, 2
years, etc. of the treatment with reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce cataplexy
by at least about
1%, at least about 5%, at least about 10%, at least about 20%, at least about
30%, at least
about 40%, at least about 50%, at least about 60%, at least about 70%, at
least about 80%, at
least about 90%, about 1-5%, about 5-10%, about 10-20%, about 20-30%, about 30-
40%,
about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-
100%,
about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the number
of partial
cataplexy attacks by at least about 10%, at least about 20%, at least about
30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least
about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about
30-40%,
about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-
80%,
about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about
75-100%,
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at least about 1 per week, at least about 2 per week, at least about 3 per
week, at least about
4 per week, at least about 5 per week, at least about 6 per week, at least
about 7 per week,
at least about 8 per week, at least about 9 per week, at least about 10 per
week, at least about
12 per week, at least about 13 per week, at least about 14 per week, at least
about 15 per
week, at least about 16 per week, at least about 18 per week, at least about
20 per week, at
least about 22 per week, at least about 24 per week, at least about 26 per
week, at least about
28 per week, at least about 30 per week, at least about 40 per week, at least
about 50 per
week, about 1-2 per week, about 2-3 per week, about 3-4 per week, about 4-5
per week,
about 5-6 per week, about 6-7 per week, about 7-8 per week, about 8-9 per
week, about 9-
10 per week, about 10-11 per week, about 11-12 per week, about 12-13 per week,
about 13-
14 per week, about 14-15 per week, about 15-16 per week, about 16-17 per week,
about 17-
18 per week, about 18-19 per week, about 19-20 per week, about 1-10 per week,
about 10-
per week, about 20-30 per week, about 30-40 per week, about 40-50 per week,
about 50-
60 per week, or more, e.g. as compared to baseline, placebo, or some other
appropriate
15 control (including an active control, such as a stimulant (e.g.
nnethylphenidate, an
amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a tricyclic
antidepressant, an SSRI,
or an SN RI). This improvement may be observed at e.g. 1 week, 2 weeks,
overall, or at any
other relevant time, such as 1 month, 6 months, 1 year, 2 years, etc. of the
treatment with
reboxetine. This improvement with the treatment of reboxetine may be
statistically
20 significant (130.05) as compared with administering a placebo. This
improvement may be
rapid. For example, at or within one week of the treatment with reboxetine in
human beings,
the average reduction in cataplexy attacks may be at least about 10%, about 10-
20%, about
20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or about 50-
60%.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) may reduce the number
of complete
cataplexy attacks by at least about 10%, at least about 20%, at least about
30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least
about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about
30-40%,
about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-
80%,
about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about
75-100%,
at least about 1 per week, at least about 2 per week, at least about 3 per
week, at least about
4 per week, at least about 5 per week, at least about 6 per week, at least
about 7 per week,
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at least about 8 per week, at least about 9 per week, at least about 10 per
week, at least about
12 per week, at least about 13 per week, at least about 14 per week, at least
about 15 per
week, at least about 16 per week, at least about 18 per week, at least about
20 per week, at
least about 22 per week, at least about 24 per week, at least about 26 per
week, at least about
28 per week, at least about 30 per week, at least about 40 per week, at least
about 50 per
week, about 1-2 per week, about 2-3 per week, about 3-4 per week, about 4-5
per week,
about 5-6 per week, about 6-7 per week, about 7-8 per week, about 8-9 per
week, about 9-
per week, about 10-11 per week, about 11-12 per week, about 12-13 per week,
about 13-
14 per week, about 14-15 per week, about 15-16 per week, about 16-17 per week,
about 17-
10 18 per week, about 18-19 per week, about 19-20 per week, about 1-10 per
week, about 10-
per week, about 20-30 per week, about 30-40 per week, about 40-50 per week,
about 50-
60 per week, or more, e.g. as compared to baseline, placebo, or some other
appropriate
control (including an active control, such as a stimulant (e.g.
nnethylphenidate, an
amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a tricyclic
antidepressant, an SSRI,
15 or an SN RI). This improvement may be observed at e.g. 1 week, 2 weeks,
overall, or at any
other relevant time, such as 1 month, 6 months, 1 year, 2 years, etc. of the
treatment with
reboxetine. This improvement with the treatment of reboxetine may be
statistically
significant (130.05) as compared with administering a placebo. This
improvement may be
rapid. For example, at or within one week of the treatment with reboxetine in
human beings,
20 the average reduction in cataplexy attacks may be at least about 10%,
about 10-20%, about
20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or about 50-
60%.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including 5,5-reboxetine) may reduce the total
number of
cataplexy attacks (partial + complete) by at least about 10%, at least about
20%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least
about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%,
about 20-
30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%,
about 60-
70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%,
about 50-
75%, about 75-100%, about 40-60%, at least about 1 per week, at least about 2
per week, at
least about 3 per week, at least about 4 per week, at least about 5 per week,
at least about 6
per week, at least about 7 per week, at least about 8 per week, at least about
9 per week, at
least about 10 per week, at least about 12 per week, at least about 13 per
week, at least about
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14 per week, at least about 15 per week, at least about 16 per week, at least
about 18 per
week, at least about 20 per week, at least about 22 per week, at least about
24 per week, at
least about 26 per week, at least about 28 per week, at least about 30 per
week, at least about
40 per week, at least about 50 per week, at least about 60 per week, at least
about 70 per
week, at least about 80 per week, at least about 90 per week, at least about
100 per week, at
least about 110 per week, at least about 120 per week, at least about 130 per
week, at least
about 140 per week, about 10-20 per week, about 12-18 per week, about 14-16
per week,
about 1-2 per week, about 2-3 per week, about 3-4 per week, about 4-5 per
week, about 5-6
per week, about 6-7 per week, about 7-8 per week, about 8-9 per week, about 9-
10 per week,
about 10-11 per week, about 11-12 per week, about 12-13 per week, about 13-14
per week,
about 14-15 per week, about 15-16 per week, about 16-17 per week, about 17-18
per week,
about 18-19 per week, about 19-20 per week, about 1-10 per week, about 10-20
per week,
about 20-30 per week, about 30-40 per week, about 40-50 per week, about 50-60
per week,
about 60-70 per week, about 70-80 per week, about 80-90 per week, about 90-100
per week,
about 100-120 per week, about 120-140 per week, or more, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. This improvement with the treatment of
reboxetine may
be statistically significant (130.05) as compared with administering a
placebo. This
improvement may be rapid. For example, at or within one week of the treatment
with
reboxetine in human beings, the average reduction in cataplexy attacks may be
at least about
10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%,
about 45-
50%, or about 50-60%.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may result in the
proportion of patients
achieving a 50% or greater reduction in the weekly number of cataplexy attacks
that is about
40-50%, about 50-60%, about 50-55%, 55-60%, about 60-70%, about 60-95%, about
70-80%,
about 70-75%, about 75-80%, or about 74-78%, e.g. as compared to baseline,
placebo, or
some other appropriate control (including an active control, such as a
stimulant (e.g.
nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a
tricyclic
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antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. This improvement with the treatment of
reboxetine may
be statistically significant (pD2I.05) as compared with administering a
placebo.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may result in the
proportion of patients
achieving a 75% or greater reduction in the weekly number of cataplexy attacks
that is about
15-20%, about 20-30%, about 20-25%, about 25-30%, about 30-40%, about 40-50%,
about
40-45%, about 45-50%, about 50-60%, about 60-70%, about 60-95%, or about 70-
80%, e.g. as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine. This
improvement with the treatment of reboxetine may be statistically significant
(pD2I.05) as
compared with administering a placebo.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the Epworth
Sleepmess
Scae (ESS) score by at least about 10%, at least about 20%, at least about
30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least
about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about
30-40%,
about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-
100%,
about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1,
at least about
2, at least about 3, at least about 4, at least about 5, at least about 6, at
least about 7, at least
about 8, at least about 9, at least about 10, at least about 11, at least
about 12, at least about
13, at least about 14, at least about 15, at least about 16, at least about
17, at least about 18,
at least about 19, at least about 20, at least about 21, at least about 22, at
least about 23,
about 24, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7,
about 7-8, about
8-9, about 9-10, about 10-11, about 11-12, about 12-13, about 13-14, about 14-
15, about 15-
16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-
22, about 22-
23, about 23-24, about 1-4, about 4-8, about 8-12, about 12-16, about 16-20,
about 20-24,
about 1-12, or about 12-24 e.g. as compared to baseline, placebo, or some
other appropriate
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control (including an active control, such as a stimulant (e.g.
nnethylphenidate, an
amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a tricyclic
antidepressant, an SSRI,
or an SNRI). This improvement may be observed at e.g. 1 week, 2 weeks,
overall, or at any
other relevant time, such as 1 month, 6 months, 1 year, 2 years, etc. of the
treatment with
reboxetine. This improvement with the treatment of reboxetine may be
statistically
significant as compared with administering a placebo with p value of D2I.05,
0.01-0.05, <0.01,
0.005-0.01, 0.001-0.005, or about 0.003.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the weekly
number of
inadvertent naps by at least about at least about 10%, at least about 20%, at
least about 30%,
at least about 40%, at least about 50%, at least about 60%, at least about
70%, at least about
80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about
20-30%,
about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-
90%,
about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, about
20-40%,
about 30-35%, or about 30-33%, at least about 1 nap per week, at least about 2
naps per
week, at least about 3 naps per week, at least about 4 naps per week, at least
about 5 naps
per week, about 1-3 naps per week, about 2-4 naps per week, about 3-4 napes
per week,
about 3-5 naps per week, about 4-6 naps per week, about 5-6 naps per week,
e.g. as compared
to baseline, placebo, or some other appropriate control (including an active
control, such as
a stimulant (e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil,
sodium
oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). This improvement
may be observed
at e.g. 1 week, 2 weeks, overall, or at any other relevant time, such as 1
month, 6 months, 1
year, 2 years, etc. of the treatment with reboxetine. This improvement with
the treatment of
reboxetine may be statistically significant as compared with administering a
placebo with p
value of D2I.05, 0.03-0.05, 0.01-0.05, <0.01, 0.005-0.01, 0.001-0.005, about
0.003, or <0.001.
A patient may be selected for treatment based upon having a problem with
inadvertent naps,
such as inadvertent naps associated with narcolepsy (with or without
cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may result in the
proportion of patients
achieving a 50% or greater reduction in the weekly number of inadvertent naps
that is about
15-20%, about 20-30%, about 30-40%, about 30-35%, about 35-40%, about 40-50%,
about
50-60%, about 60-70%, or about 70-80%, e.g. as compared to baseline, placebo,
or some
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other appropriate control (including an active control, such as a stimulant
(e.g.
nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a
tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. This improvement with the treatment of
reboxetine may
be statistically significant (pD2I.05) as compared with administering a
placebo.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the
Maintenance of
Wakefulness Test (MWT) score by at least about 10%, at least about 20%, at
least about 30%,
at least about 40%, at least about 50%, at least about 60%, at least about
70%, at least about
80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about
20-30%,
about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-
90%,
about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at
least about
1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4
minutes, at least
about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least
about 8 minutes,
at least about 9 minutes, at least about 10 minutes, at least about 11
minutes, at least about
12 minutes, at least about 13 minutes, at least about 14 minutes, at least
about 15 minutes,
at least about 16 minutes, at least about 17 minutes, at least about 18
minutes, at least about
19 minutes, at least about 20 minutes, about 1-2 minutes, about 2-3 minutes,
about 3-4
minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8
minutes, about
8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes,
about 12-13
minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about
16-17
minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about
20-21
minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about
24-26
minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16
minutes,
about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes, e.g. as
compared to
baseline, placebo, or some other appropriate control (including an active
control, such as a
stimulant (e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil,
sodium oxybate,
a tricyclic antidepressant, an SSRI, or an SNRI). This improvement may be
observed at e.g. 1
week, 2 weeks, overall, or at any other relevant time, such as 1 month, 6
months, 1 year, 2
years, etc. of the treatment with reboxetine.
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In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may improve cognitive
function, e.g.
over a 1-week period or a 2-week period, as measured by the Ability to
Concentrate item of
the NSAQ. For example, the improvement in the ability to concentrate score on
a 5-point
scale (1=very good, 2=good, 3=average, 4=poor, and 5=very poor) may be at
least about -0.1,
at least about -0.2, at least about -0.3, about -0.05 to about -0.5, about -
0.05 to about -0.2,
about -0.2 to about -0.3, about 0.3 to about -0.4, about -0.4 to about -0.5,
about -0.5 to
-0.6, about -0.6 to about -0.7, or about -0.7 to about -0.8, e.g. as compared
to baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI), wherein "-" represents reduction in the
ability to
concentrate score. In some embodiments, the number of patients having an
ability to
concentrate that is "very good" or "good" may be at least about 20%, at least
25%, at least
about 30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at
least about 80%, at least about 90%, at least about 95%, about 20-30%, about
30-40%, about
30-35%, about 35-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%,
about
60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 15-25%,
about
25-50%, about 50-75%, or about 75-100%, about 40-60%, about 35-40%, or about
40-45%,
e.g. as compared to baseline, placebo, or some other appropriate control
(including an active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine. This
improvement with the treatment of reboxetine may be statistically significant
(pD2I.05) as
compared with administering a placebo, e.g. p=0.01-0.05, <0.01, 0.001-0.01,
0.001-0.005,
0.005-0.01, 0.002 or 0.007. A patient may be selected for treatment based upon
having
reduced cognitive function, such as reduced cognitive function associated with
narcolepsy
(with or without cataplexy).
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," "poor," or "very poor," and one week after
the start of the
treatment, the human being has an ability to concentrate that is "good" or
"very good."
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In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," and one week after the start of the
treatment, the human
being has an ability to concentrate that is "good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," and one week after the start of the
treatment, the human
being has an ability to concentrate that is "very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "poor," and one week after the start of the treatment,
the human being
has an ability to concentrate that is "good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "poor," and one week after the start of the treatment,
the human being
has an ability to concentrate that is "very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "very poor," and one week after the start of the
treatment, the human
being has an ability to concentrate that is "good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "very poor," and one week after the start of the
treatment, the human
being has an ability to concentrate that is "very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," "poor," or "very poor," and two weeks after
the start of the
treatment, the human being has an ability to concentrate that is "good" or
"very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," and two weeks after the start of the
treatment, the human
being has an ability to concentrate that is "good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "average," and two weeks after the start of the
treatment, the human
being has an ability to concentrate that is "very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "poor," and two weeks after the start of the treatment,
the human
being has an ability to concentrate that is "good."
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In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "poor," and two weeks after the start of the treatment,
the human
being has an ability to concentrate that is "very good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "very poor," and two weeks after the start of the
treatment, the human
being has an ability to concentrate that is "good."
In some embodiments, prior to the start of treatment, the human being has an
ability
to concentrate that is "very poor," and two weeks after the start of the
treatment, the human
being has an ability to concentrate that is "very good."
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may improve sleep
quality. For
example, the patient may report improved sleep quality. In some embodiments,
the number
of patients reporting improved sleep quality may be at least about 20%, at
least about 30%,
at least about 40%, at least about 50%, at least about 60%, at least about
70%, at least about
80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about
40-50%,
about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-
25%,
about 25-50%, about 50-75%, or about 75-100%, about 40-60%, about 42-47%, e.g.
as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). In some
embodiments, a patient may have an improvement in sleep quality that is at
least about 20%,
at least about 30%, at least about 40%, at least about 50%, at least about
60%, at least about
70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%,
about 20-
30%, about 30-40%, about 40-50%, about 40-45%, about 45-40%, about 50-60%,
about 60-
70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%,
about 50-
75%, or about 75-100%, about 40-60%, about 42-47%, or about 45%, e.g. as
compared to
baseline, placebo, or some other appropriate control (including an active
control, such as a
stimulant (e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil,
sodium oxybate,
a tricyclic antidepressant, an SSRI, or an SNRI). This improvement may be
observed at e.g. 1
week, 2 weeks, overall, or at any other relevant time, such as 1 month, 6
months, 1 year, 2
years, etc. of the treatment with reboxetine. This improvement with the
treatment of
reboxetine may be statistically significant (pD2I.05) as compared with
administering a placebo,
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e.g. p=0.01-0.05, <0.01, 0.001-0.01, 0.001-0.005, 0.005-0.01, or 0.007. A
patient may be
selected for treatment based upon having a problem with sleep quality, such as
a problem
with sleep quality associated with narcolepsy (with or without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the number
of awakenings
at night, e.g. as reported by the patient. For example, the number of patients
reporting a
reduction in the number of awakenings at night may be at least about 20%, at
least about
30%, at least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least
about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%,
about 40-
50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%,
about 1-
25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60%, about 42-47%,
e.g. as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). In some
embodiments, a patient may have a reduction in the number of awakenings at
night that is at
least about 20%, at least about 30%, at least about 40%, at least about 50%,
at least about
60%, at least about 70%, at least about 80%, at least about 90%, at least
about 95%, about
10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%,
about
70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%,
or about
75-100%, about 40-60%, about 42-47%, or about 30%, e.g. as compared to
baseline, placebo,
or some other appropriate control (including an active control, such as a
stimulant (e.g.
nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a
tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. This improvement with the treatment of
reboxetine may
be statistically significant (pD2I.05) as compared with administering a
placebo, e.g. p=0.01-
0.05, 0.04-0.05, or 0.044. A patient may be selected for treatment based upon
having a
problem with awakenings at night, such as a problem with awakenings at night
associated
with narcolepsy (with or without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the number
of sleep
paralysis episodes, e.g. as reported by the patient. For example, the number
of patients
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having a reduction in the number of sleep paralysis episodes may be at least
about 20%, at
least about 30%, at least about 40%, at least about 50%, at least about 60%,
at least about
70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%,
about 30-
40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,
about 90-
100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 50-70%,
about
52-57%, e.g. as compared to baseline, placebo, or some other appropriate
control (including
an active control, such as a stimulant (e.g. nnethylphenidate, an
amphetamine), nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). In some
embodiments, a patient may have a reduction in the number of sleep paralysis
episodes that
is at least about 20%, at least about 30%, at least about 40%, at least about
50%, at least
about 60%, at least about 70%, at least about 80%, at least about 90%, at
least about 95%,
about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-
70%,
about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-
75%, or
about 75-100%, about 50-70%, about 52-57%, or about 55%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon having
a problem with sleep paralysis, such as a problem with sleep paralysis
associated with
narcolepsy (with or without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the number
of hypnagogic
hallucinations, e.g. as reported by the patient. For example, the number of
patients having a
reduction in the number of hypnagogic hallucinations may be at least about
10%, at least
about 20%, at least about 30%, at least about 40%, about 20-30%, about 30-40%,
about 40-
50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%,
about 1-
25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%,
e.g. as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). In some
embodiments, a patient may have a reduction in the number of hypnagogic
hallucinations
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that is at least about 10%, at least about 20%, at least about 30%, at least
about 40%, about
10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%,
about
70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%,
or about
75-100%, about 30-50%, about 35-45%, or about 40%, e.g. as compared to
baseline, placebo,
or some other appropriate control (including an active control, such as a
stimulant (e.g.
nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a
tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon
problems with hypnagogic hallucinations, such as hypnagogic hallucinations
associated with
narcolepsy (with or without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the
cataplexy score on the
UNS by at least about 10%, at least about 20%, at least about 30%, at least
about 40%, at least
about 45%, at least about 50%, at least about 60%, at least about 70%, at
least about 80%, at
least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%,
about 30-
40%, about 40-50%, about 45-50%, about 50-60%, about 60-70%, about 70-80%,
about 80-
90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%,
at least
about 1, at least about 2, at least about 3, at least about 4, at least about
5, at least about 6,
at least about 7, at least about 8, at least about 9, at least about 10, about
11, about 2-3,
about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10,
about 2-4, about
4-6, about 6-8, about 8-10, about 10-11, about 2-6, or about 6-10, about 5-11,
e.g. as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may increase sleep
latency on the
MSLT by at least about 30%, at least about 50%, at least about 60%, at least
about 70%, at
least about 80%, at least about 90%, at least about 95%, about 50-60%, more
than 55%, about
60-70%, about 70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-
100%, at
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least about 1 minute, at least about 2 minutes, at least about 3 minutes, more
than 3 minutes,
at least about 4 minutes, at least about 5 minutes, at least about 6 minutes,
at least about 7
minutes, at least about 8 minutes, at least about 9 minutes, at least about 10
minutes, at least
about 11 minutes, at least about 12 minutes, at least about 13 minutes, at
least about 14
minutes, at least about 15 minutes, at least about 16 minutes, at least about
17 minutes, at
least about 18 minutes, at least about 19 minutes, at least about 20 minutes,
about 1-2
minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6
minutes, about
6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about
10-11
minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about
14-15
minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about
18-19
minutes, about 19-20 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12
minutes,
about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20
minutes, e.g.
as compared to baseline, placebo, or some other appropriate control (including
an active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
.. arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the Patient
Global
Impression of Severity (PGI-S) score by at least about 10%, at least about
20%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least
about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%,
about 20-
30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%,
about 80-
90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, at
least
about 0.1, at least about 0.5, at least about 1, at least about 1.5, at least
about 2, at least
about 2.5, at least about 3, at least about 3.5, about 0.1-0.5, about 0.5-1,
about 1-1.5, about
1.5-2, about 2-2.5, about 2.5-3, about 3-3.5, or about 3.5-4, e.g. as compared
to baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine.
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In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may result in a
Patient Global
Impression of Change (PGI-C) score that is about 1-2, about 2-3, or about 3-4,
or is reduced
by at least about 10%, at least about 20%, at least about 30%, at least about
40%, at least
.. about 50%, at least about 60%, at least about 70%, at least about 80%, at
least about 90%, at
least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about
40-50%,
about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-
25%,
about 25-50%, about 50-75%, about 75-100%, at least about 0.5, at least about
1, at least
about 2, at least about 3, at least about 4, at least about 5, about 0.5-1,
about 1-2, about 2-3,
about 3-4, about 4-5, or about 5-6, e.g. as compared to placebo, or some other
appropriate
control (including an active control, such as a stimulant (e.g.
nnethylphenidate, an
amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a tricyclic
antidepressant, an SSRI,
or an SNRI). This improvement may be observed at e.g. 1 week, 2 weeks,
overall, or at any
other relevant time, such as 1 month, 6 months, 1 year, 2 years, etc. of the
treatment with
reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce the
Hamilton Depression
Rating Scale (HAM-D) score by at least about 10%, at least about 20%, at least
about 30%, at
least about 40%, at least about 50%, at least about 60%, at least about 70%,
at least about
80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about
20-30%,
about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-
90%,
about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at
least about
1, at least about 2, at least about 3, at least about 4, at least about 5, at
least about 6, at least
about 7, at least about 8, at least about 9, at least about 10, at least about
11, at least about
12, at least about 13, at least about 14, at least about 15, at least about
16, at least about 17,
at least about 18, at least about 19, at least about 20, at least about 21, at
least about 22, at
least about 23, at least about 30, at least about 40, about 1-2, about 2-3,
about 3-4, about 4-
5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about
11-12, about
12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about
18-19, about
19-20, about 20-21, about 21-22, about 22-23, about 23-27, about 27-30, about
30-35, about
35-40, about 40-45, about 45-50, about 1-4, about 4-8, about 8-12, about 12-
16, about 16-
20, about 20-24, about 24-30, about 30-40, about 40-50. about 1-12, about 12-
24, about 24-
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36, or about 36-50 e.g. as compared to baseline, placebo, or some other
appropriate control
(including an active control, such as a stimulant (e.g. nnethylphenidate, an
amphetamine),
nnodafanil, arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI,
or an SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce nightmares
or unpleasant
dreams (such as frequent nightmares and frequent unpleasant dreams) by at
least about 1%,
at least about 10%, at least about 20%, at least about 30%, at least about
40%, at least about
50%, at least about 60%, at least about 70%, at least about 80%, at least
about 90%, at least
about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-
50%, about
50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%,
about
25-50%, about 50-75%, or about 75-100%, e.g. as compared to baseline, placebo,
or some
other appropriate control (including an active control, such as a stimulant
(e.g.
nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a
tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon having
a problem with nightmares or unpleasant dreams (such as frequent nightmares
and frequent
unpleasant dreams), including nightmares or unpleasant dreams (such as
frequent
nightmares and frequent unpleasant dreams) associated with narcolepsy (with or
without
cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce
hallucinations by at least
-- about 1%, at least about 10%, at least about 20%, at least about 30%, at
least about 40%, at
least about 50%, at least about 60%, at least about 70%, at least about 80%,
at least about
90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-
40%, about
40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%,
about
1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
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weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon having
a problem with hallucinations, such as hallucinations associated with
narcolepsy (with or
without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce sleep
paralysis by at least
about 1%, at least about 10%, at least about 20%, at least about 30%, at least
about 40%, at
least about 50%, at least about 60%, at least about 70%, at least about 80%,
at least about
90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-
40%, about
40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%,
about
1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon having
a problem with sleep paralysis, such as sleep paralysis associated with
narcolepsy (with or
without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce disturbed
nocturnal sleep
by at least about 1%, at least about 10%, at least about 20%, at least about
30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least
about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about
30-40%,
about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-
100%,
about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine. A patient may be selected for treatment
based upon having
a problem with disturbed nocturnal sleep, such as disturbed nocturnal sleep
associated with
narcolepsy (with or without cataplexy).
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In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce narcolepsy-
related
accidents by at least about 1%, at least about 10%, at least about 20%, at
least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least about 70%,
at least about
80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about
20-30%,
about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-
90%,
about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g.
as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any other
relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine. A patient
may be selected for treatment based upon having a problem with narcolepsy-
related
accidents (with or without cataplexy).
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce narcolepsy-
related injuries
by at least about 1%, at least about 10%, at least about 20%, at least about
30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, at least
about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about
30-40%,
about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-
100%,
about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to
baseline,
placebo, or some other appropriate control (including an active control, such
as a stimulant
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI). This improvement may be observed at e.g.
1 week, 2
weeks, overall, or at any other relevant time, such as 1 month, 6 months, 1
year, 2 years, etc.
of the treatment with reboxetine.
In some embodiments, administering an antidepressant, including a
norepinephrine
inhibitor such as reboxetine (including S,S-reboxetine) may reduce narcolepsy-
related fatal
accidents by at least about 1%, at least about 10%, at least about 20%, at
least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least about 70%,
at least about
80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about
20-30%,
about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-
90%,
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about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g.
as
compared to baseline, placebo, or some other appropriate control (including an
active
control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an
SNRI). This
-- improvement may be observed at e.g. 1 week, 2 weeks, overall, or at any
other relevant time,
such as 1 month, 6 months, 1 year, 2 years, etc. of the treatment with
reboxetine. A patient
may be selected for treatment based upon being at risk for narcolepsy-related
fatal accidents
(for narcolepsy patients with or without cataplexy).
Reboxetine (with the structure shown below) (including S,S-reboxetine, e.g.
with the
structure shown below) is a highly selective and potent norepinephrine
reuptake inhibitor
that has the potential to address the key symptoms of narcolepsy, such as
cataplexy or EDS.
Unlike existing treatments for narcolepsy, reboxetine is not a controlled
substance. Thus, the
treatment with reboxetine would not be scheduled.
.
0 0¨/
0
( ____________ NH (reboxetine)
0
H
0 =
O 0 -
H
NH= MeS03H
(S,S-reboxetine)
Unless otherwise indicated, any reference to a compound herein, such as
reboxetine,
by structure, name, or any other means, includes pharmaceutically acceptable
salts; free acids
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or bases; alternate solid forms, such as polynnorphs, solvates, hydrates,
etc.; tautonners;
enantionners; deuterium modified compounds, such as deuterium modified
reboxetine; or
any chemical species that may rapidly convert to a compound described herein
under
conditions in which the compounds are used as described herein.
In some embodiments, reboxetine is in a salt form, a free base form, or may
contain
an excess (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at
least 95%, at least 97%,
or at least 99%) of (+)-reboxetine, also referred to as S,S-reboxetine or
esreboxetine; or an
excess (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at least
95%, at least 97%,
or at least 99%) of (¨)-reboxetine.
For treatment of narcolepsy, the reboxetine (including S,S-reboxetine) may be
administered in a manner that results in 1) a first local maximum in
reboxetine (including S,S-
reboxetine) plasma concentration and 2) a second local maximum in reboxetine
(including
S,S-reboxetine) plasma concentration.
There are many potential ways that reboxetine (including S,S-reboxetine) could
be
administered in a manner that results in a first local maximum in reboxetine
(including S,S-
reboxetine) plasma concentration and a second local maximum in reboxetine
(including S,S-
reboxetine) plasma concentration. A local maximum described herein is a
maximum of a
plasma concentration in a time period of interest in an individual patient,
which is not
necessarily the Cmax. The local maximum may be lower or the same as Cmax. One
potential
way to administer reboxetine (including S,S-reboxetine) in a manner that
results in a first local
maximum in reboxetine (including S,S-reboxetine) plasma concentration and a
second local
maximum in reboxetine (including S,S-reboxetine) plasma concentration is to
administer a
first dosage form containing reboxetine (including S,S-reboxetine) and, at a
later time, a
second dosage form containing reboxetine (including S,S-reboxetine). The doses
are
administered at times that result in a first local maximum in reboxetine
(including S,S-
reboxetine) plasma concentration and a second local maximum in reboxetine
(including S,S-
reboxetine) plasma concentration. For
example, the second dosage form may be
administered less than half a day after the first dosage form, e.g. about 1-8
hours, about 8-12
hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours,
about 4-5 hours,
about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4
hours, about
3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10
hours, after the
first dosage form, or any time period in a range bounded by any of these
values.
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Another method involves administering a single dosage form comprising a first
release
component and a second release component. Both the first release component and
the
second release component comprise reboxetine (including S,S-reboxetine).
In some embodiments, the first dosage form administered in a day, the only
dosage
form administered during the day, or the first of two or more dosage forms
administered
during the day, is administered shortly after waking, such as within about 3
hours, within
about 2 hours, within about 1.5 hours, within about 1 hour, within about 30
minutes, or within
about 15 minutes of waking from an overnight sleep.
For a single dosage form comprising a first release component and a second
release
component that is administered in a day, the first release component may
release reboxetine
(including S,S-reboxetine), may begin releasing reboxetine (including S,S-
reboxetine), or may
result in a first local maximum in the plasma concentration of reboxetine
(including S,S-
reboxetine), about 0-30 minutes, about 30-60 minutes, about 60-90 minutes, or
about 90-
120 minutes after the dosage form is orally administered, or any time period
in a range
bounded by any of these values. The second release component may release
reboxetine
(including S,S-reboxetine) after the first release component releases
reboxetine (including
S,S-reboxetine), or may cause an increase of reboxetine (including S,S-
reboxetine) plasma
concentration or a second local maximum in the plasma concentration of
reboxetine
(including S,S-reboxetine), that is about 1-10 hours, about 2-6 hours, about 1-
2 hours, about
2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours,
about 1-3
hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours,
about 6-8 hours,
or about 7-10 hours after reboxetine (including S,S-reboxetine) is first
released from the first
release component, or after the first local maximum in the plasma
concentration of
reboxetine (including S,S-reboxetine), or at any time in a range bounded by
any of these
values.
The first release component and the second release component may be
incorporated
into one single dosage form (such as a pill, tablet, capsule, caplet, or
cachou). In one
embodiment, the first release component would be located in one of the outer
layers of the
dosage form and the second release component would be located in one of the
inner layers
of the same dosage form.
In another embodiment, the first release component is located in a first layer
of the
dosage form, and the second release component is located in a second layer of
the same
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dosage form. The two layers are distinct and may or may not be in contact with
one another.
In some embodiments, the two layers are stacked on top of one another and
physically bound
in a bi-layer structure (e.g. where the largest surfaces of the two layers
contact one another,
or the layers are thin compared to the other dimensions of the layers). In
some embodiments,
the two layers are positioned next to one another and physically bound in a bi-
layer structure
(e.g. where the layers are thicker than other dimensions of the layers).
In another embodiment, the first release component and the second release
component may be constructed separately in their own specific granules,
particles, or the like,
wherein the first release component particles are formulated to release
reboxetine (including
S,S-reboxetine) before the second release component particles release
reboxetine (including
S,S-reboxetine) and wherein both the first release component particles and the
second
release component particles are combined together into a single dosage form,
such as a
capsule, pill, tablet, caplet, cachou or the like, and the two release
components may or may
not be physically bound to one another.
In some embodiments, the first local maximum plasma concentration of
reboxetine
(including S,S-reboxetine) occurs about 1-30 minutes, about 30-60 minutes,
about 1-2 hours,
about 2-3 hours, or about 3-4 hours after the single dosage form or the first
dosage form is
administered, or at any time in a range bounded by any of these values.
Generally, the second
local maximum plasma concentration of reboxetine (including S,S-reboxetine)
occurs less
than half a day after the first local maximum plasma concentration of
reboxetine (including
S,S-reboxetine), such as about 1-10 hours, about 1-2 hours, about 2-6 hours,
about 2-3 hours,
about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8
hours, about
1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours,
about 6-8
hours, or about 7-10 hours, after the first local maximum plasma concentration
of reboxetine
(including S,S-reboxetine), or any time period in a range bounded by any of
these values.
For dosage forms containing a first release component and a second release
component, the first release component is associated with the first local
maximum in
reboxetine (including S,S-reboxetine) plasma concentration in that the first
release
component releases the reboxetine (including S,S-reboxetine) that contributes
to the first
local maximum in reboxetine (including S,S-reboxetine) plasma concentration.
For example,
the first release component could release reboxetine (including S,S-
reboxetine) faster or
sooner than the second release component, so that most of the reboxetine
(including S,S-
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reboxetine) contributing to the first local maximum plasma concentration of
reboxetine
(including S,S-reboxetine) that was released from the first release component.
For dosage forms containing a first release component and a second release
component, the second release component is associated with the second local
maximum in
reboxetine (including S,S-reboxetine) plasma concentration in that the second
release
component releases the reboxetine (including S,S-reboxetine) that contributes
to the second
local maximum in reboxetine (including S,S-reboxetine) plasma concentration.
For example,
the second release component could delay release of its reboxetine (including
S,S-reboxetine)
so that at a time when the reboxetine (including S,S-reboxetine) plasma
concentration is
.. decreasing after the first local maximum, the second release component
releases a sufficient
amount of reboxetine (including S,S-reboxetine) to again increase the plasma
concentration
of reboxetine (including S,S-reboxetine) so that the second local maximum in
reboxetine
(including S,S-reboxetine) plasma concentration is achieved.
For dosage forms containing a first release component and a second release
component, any suitable amount of reboxetine (including S,S-reboxetine) may be
present in
the first release component, such as about 1-10 mg, about 0.1-2 mg, about 0.5-
1.5 mg, about
1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about
3.5-4.5 mg,
about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg,
about 8-9 mg,
about 9-10 mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-
7 mg, about
7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 nnnnol, about 0.006-0.009
nnnnol, about
0.009-0.012 nnnnol, about 0.012-0.015 nnnnol, about 0.015-0.018 nnnnol, about
0.018-0.021
nnnnol, about 0.021-0.024 nnnnol, about 0.024-0.027 nnnnol, about 0.027-0.03
nnnnol, about
0.03-0.033 nnnnol, or any amount in a range bounded by any of these values.
For dosage forms containing a first release component and a second release
component, any suitable amount of reboxetine (including S,S-reboxetine) may be
present in
the second release component, such as about 0.1-2 mg, about 0.5-1.5 mg, about
1-3 mg,
about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg,
about 2-4
mg, about 3-5 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6
mg, about 4-
6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 5-7 mg,
about 7-10
mg, about 4 mg, about 5 mg, about 0.0003-0.006 nnnnol, about 0.006-0.009
nnnnol, about
0.009-0.012 nnnnol, about 0.012-0.015 nnnnol, about 0.015-0.018 nnnnol, about
0.018-0.021
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nnnnol, about 0.021-0.024 nnnnol, about 0.024-0.027 nnnnol, about 0.027-0.03
nnnnol, about
0.03-0.033 nnnnol, or any amount in a range bounded by any of these values.
In some embodiments, the first release component may contain more reboxetine
(including S,S-reboxetine) than the second release component, such as about 10-
20% more,
about 20-30% more, or about 30-40% more reboxetine (including S,S-reboxetine),
than the
second release component.
While the dosing schedules given above may be useful in many situations, the
daily
dosing schedule may be different than described above. For example, a once a
day dose may
be administered. A twice daily dose may be administered in any suitable way,
such as in the
morning and the evening, in a manner described above, or some other way.
In some embodiments, the daily dose of reboxetine (including S,S-reboxetine),
may be
about 0.5-1 mg, about 1-1.5 mg, about 1.5-2 mg, about 1-2 mg, about 2-3 mg,
about 3-4 mg,
about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-
10 mg, about
10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg,
about 15-16
mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg,
about 14-
17 mg, about 17-20 mg, about 8-10 mg, about 8-12 mg, about 0.0015-0.003
nnnnol, about
0.003-0.0045 nnnnol, about 0.0045-0.006 nnnnol, about 0.003-0.006 nnnnol,
about 0.006-0.009
nnnnol, about 0.009-0.012 nnnnol, about 0.012-0.015 nnnnol, about 0.015-0.018
nnnnol, about
0.018-0.021 nnnnol, about 0.021-0.024 nnnnol, about 0.024-0.027 nnnnol, about
0.027-0.03
nnnnol, about 0.03-0.033 nnnnol, about 0.033-0.036 nnnnol, about 0.036-0.039
nnnnol, about
0.039-0.042 nnnnol, about 0.042-0.045 nnnnol, about 0.045-0.048 nnnnol, about
0.048-0.051
nnnnol, about 0.051-0.054 nnnnol, about 0.054-0.057 nnnnol, about 0.057-0.06
nnnnol, about
0.06-0.063 nnnnol, about 0.063-0.066 nnnnol, about 0.066-0.069 nnnnol, about
0.006-0.01
nnnnol, about 0.01-0.02 nnnnol, about 0.02-0.03 nnnnol, about 0.03-0.04
nnnnol, about 0.04-0.05
nnnnol, about 0.05-0.06 nnnnol, about 0.06-0.07 nnnnol, or about 0.07-0.08
nnnnol. The daily
dose is the total amount of reboxetine administered in a single day. The daily
dose may be
administered for at least about 1 week, at least about 2 weeks, at least about
3 weeks, at least
about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about
7 weeks, at least
about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about
11 weeks, at
least about 12 weeks, at least 4 months, at least 5 months, at least about 6
months, at least
about 7 months, at least about 8 months, at least about 9 months, at least
about 10 months,
at least about 11 months, at least about 12 months, at least 1.5 years, at
least 2 years, at least
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about 3 years, at least about 4 years, at least about 5 years, at least about
10 years, at least
about 20 years, or longer. In some embodiments, the daily dose is administered
for up to
about 6 months, up to about 1 year, up to about 2 years, up to about 5 years,
up to about 10
years, up to about 20 years, up to about 40 years, up to about 60 years, or up
to about 90
years.
The dose of reboxetine (including S,S-reboxetine) may gradually increase over
time,
such as for 1, 2, 3, 4, 5, 6, or 7 days, to a maintenance dose, which is a
total dose given each
day (e.g. a 10 mg maintenance dose could be a once daily 10 mg dose, a 6 mg
morning dose
and a 4 mg afternoon dose, or 5 mg given twice a day for a total of 10 mg per
day). In some
embodiments, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg,
about 5-6
mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg,
about 11-12
mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-
17 mg,
about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, about 14-17 mg,
about 17-20
mg, about 8-10 mg, about 8-12 mg, about 0.006-0.009 nnnnol, about 0.009-0.012
nnnnol, about
0.012-0.015 nnnnol, about 0.015-0.018 nnnnol, about 0.018-0.021 nnnnol, about
0.021-0.024
nnnnol, about 0.024-0.027 nnnnol, about 0.027-0.03 nnnnol, about 0.03-0.033
nnnnol, about
0.033-0.036 nnnnol, about 0.036-0.039 nnnnol, about 0.039-0.042 nnnnol, about
0.042-0.045
nnnnol, about 0.045-0.048 nnnnol, about 0.048-0.051 nnnnol, about 0.051-0.054
nnnnol, about
0.054-0.057 nnnnol, about 0.057-0.06 nnnnol, about 0.06-0.063 nnnnol, about
0.063-0.066
nnnnol, about 0.066-0.069 nnnnol, about 0.006-0.01 nnnnol, about 0.01-0.02
nnnnol, about 0.02-
0.03 nnnnol, about 0.03-0.04 nnnnol, about 0.04-0.05 nnnnol, about 0.05-0.06
nnnnol, about 0.06-
0.07 nnnnol, or about 0.07-0.08 nnnnol. In some embodiments, a first dose,
e.g. administered
in the morning, may contain more reboxetine (including S,S-reboxetine) than a
second dose
administered in a day, e.g. administered in the afternoon. For example, the
first dose of the
day, e.g. administered in the morning, may have about 10-20% more, about 20-
30% more, or
about 30-40% more reboxetine (including S,S-reboxetine) than the second dose
of the day,
e.g. administered in the afternoon. The maintenance dose may be administered
for at least
about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4
weeks, at least
about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about
8 weeks, at least
about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least
about 12 weeks, at
least 4 months, at least 5 months, at least about 6 months, at least about 7
months, at least
about 8 months, at least about 9 months, at least about 10 months, at least
about 11 months,
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at least about 12 months, at least 1.5 years, at least 2 years, at least about
3 years, at least
about 4 years, at least about 5 years, at least about 10 years, at least about
20 years, or longer.
In some embodiments, the maintenance dose is administered for up to about 6
months, up
to about 1 year, up to about 2 years, up to about 5 years, up to about 10
years, up to about
20 years, up to about 40 years, up to about 60 years, or up to about 90 years.
In some embodiments, a patient receives about 110-130 mg of reboxetine
(including
S,S-reboxetine) over a period of two weeks.
In some embodiments, the first release component provides immediate release of
reboxetine (including S,S-reboxetine). In some embodiments, the first release
component
provides delayed release of reboxetine (including S,S-reboxetine). In some
embodiments, the
first release component provides sustained release of reboxetine (including
S,S-reboxetine).
In some embodiments, the second release component provides immediate release
of
reboxetine (including S,S-reboxetine). In some embodiments, the second release
component
provides delayed release of reboxetine (including S,S-reboxetine). In some
embodiments, the
second release component provides sustained release of reboxetine (including
S,S-
reboxetine).
In some embodiments, the first release component provides immediate release of
reboxetine (including S,S-reboxetine), and the second release component
provides delayed
release of reboxetine (including S,S-reboxetine). In some embodiments, the
first release
component provides immediate release of reboxetine (including S,S-reboxetine),
and the
second release component provides sustained release of reboxetine (including
S,S-
reboxetine).
With respect to methods wherein the reboxetine (including S,S-reboxetine) is
administered in a first dosage form containing reboxetine (including S,S-
reboxetine) and a
second dosage form containing reboxetine (including S,S-reboxetine), any
suitable amount of
reboxetine (including S,S-reboxetine) may be present in the first dosage form,
such as about
1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about
1-2 mg,
about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5
mg, about 4-
5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9
mg, about 9-
10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg,
about 4 mg,
about 5 mg, about 0.0003-0.006 nnnnol, about 0.006-0.009 nnnnol, about 0.009-
0.012 nnnnol,
about 0.012-0.015 nnnnol, about 0.015-0.018 nnnnol, about 0.018-0.021 nnnnol,
about 0.021-
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0.024 nnnnol, about 0.024-0.027 nnnnol, about 0.027-0.03 nnnnol, about 0.03-
0.033 nnnnol, or
any amount in a range bounded by any of these values.
With respect to methods wherein the reboxetine (including S,S-reboxetine) is
administered in a first dosage form containing reboxetine (including S,S-
reboxetine) and a
second dosage form containing reboxetine (including S,S-reboxetine), any
suitable amount of
reboxetine (including S,S-reboxetine) may be present in the second dosage
form, such as
about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg,
about 1.5-
2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about
4-5 mg, about
4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10
mg, about
2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg,
about 5 mg,
about 0.0003-0.006 nnnnol, about 0.006-0.009 nnnnol, about 0.009-0.012 nnnnol,
about 0.012-
0.015 nnnnol, about 0.015-0.018 nnnnol, about 0.018-0.021 nnnnol, about 0.021-
0.024 nnnnol,
about 0.024-0.027 nnnnol, about 0.027-0.03 nnnnol, about 0.03-0.033 nnnnol, or
any amount in
a range bounded by any of these values.
In some embodiments, the first dosage form may contain more reboxetine
(including
S,S-reboxetine) than the dosage form, such as about 10-20% more, about 20-30%
more, or
about 30-40% more reboxetine (including S,S-reboxetine) than the second dosage
form.
In some embodiments, the first dosage form provides immediate release of
reboxetine (including S,S-reboxetine). In some embodiments, the first dosage
form provides
delayed release of reboxetine (including S,S-reboxetine). In some embodiments,
the first
dosage form provides sustained release of reboxetine (including S,S-
reboxetine).
In some embodiments, the second dosage form provides immediate release of
reboxetine (including S,S-reboxetine). In some embodiments, the second dosage
form
provides delayed release of reboxetine (including S,S-reboxetine). In some
embodiments, the
second dosage form provides sustained release of reboxetine (including S,S-
reboxetine).
With respect to single dosage forms containing both a first release component
and a
second release component, in some embodiments, the single dosage is
administered within
two hours of waking from an overnight sleep.
For some embodiments wherein more than one dosage form is given, the first
dosage
form may be administered within two hours of waking from an overnight sleep.
There are many factors that can affect the overall time required for a drug
substance
such as reboxetine (including S,S-reboxetine) to be fully absorbed and/or
reach a maximum
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plasma concentration in a human being. Some of these factors include a human
patient's
age, weight, gender, level of stress, stomach contents, stomach pH level, and
the presence of
other medications. The time required to reach a maximum plasma concentration
of the drug
such as reboxetine (including 5,5-reboxetine) may also be affected by the time
of the day
taken the drug such as reboxetine (including 5,5-reboxetine) and the level of
physical activity
of the human patient. Another factor that can affect the time required to
reach a maximum
plasma concentration of the drug such as reboxetine (including 5,5-reboxetine)
is the
presence or absence of a controlled release coating on the drug such as
reboxetine (including
5,5-reboxetine).
Controlled release includes: immediate release of drug substance such as
reboxetine
(including 5,5-reboxetine) at a certain time or in a certain area of the body;
delayed release
of a drug substance; sustained release of drug substance at a certain time or
place in the body;
or an extended release of a drug substance such as reboxetine (including 5,5-
reboxetine).
Reboxetine (including 5,5-reboxetine) is normally rapidly absorbed in human
patients,
reaching a maximum plasma concentration in about 2-4 hours. To achieve a delay
in the time
required to reach a maximum plasma concentration, a controlled release coating
or mixture
may be employed.
Delayed release is a general drug delivery term that describes the form of an
oral
medication that does not immediately discharge its active drug component in
the mouth or
in the stomach of a patient. While there may be many ways to achieve delayed
release,
delayed release of reboxetine (including 5,5-reboxetine) may be achieved by
completely or
partially surrounding the reboxetine (including 5,5-reboxetine), e.g. in the
second release
component, with a coating or layer (e.g. an inner controlled release coating)
that does not
immediately dissolve when swallowed. For example, the material of the coating
or layer may
slowly dissolve in the stomach, and/or slowly disintegrate by chemical
reaction, such as by
hydrolysis, in the stomach until the layer can no longer prevent the
reboxetine (including S,S-
reboxetine) from coming into contact with the gastric fluid.
In some embodiments, the delayed release coating ensures delivery through the
stomach and into the intestines. Once in the duodenum, the coating may begin
to break
down and begin to release reboxetine (including 5,5-reboxetine). In some
cases, the
reboxetine (including 5,5-reboxetine) may be completely released in the
duodenum. In some
embodiments, the reboxetine (including 5,5-reboxetine) may be partially
released in the
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duodenum, and partially released in the jejunum. In some cases, the reboxetine
(including
S,S-reboxetine) may be completely released in the jejunum. In some cases, the
reboxetine
(including S,S-reboxetine) may be partially released in the jejunum and
partially released in
the ilium. In some cases, the reboxetine (including S,S-reboxetine) may be
completely
released in the ilium. In some cases, the reboxetine (including S,S-
reboxetine) may be partially
released in the duodenum, the jejunum, and the ilium. In some embodiments, the
reboxetine
(including S,S-reboxetine) may be partially released in the ilium, and
partially released in the
colon. In some cases, the reboxetine (including S,S-reboxetine) may be
completely released
in the colon.
The time of the delayed release, e.g. between release of the first reboxetine
(including
S,S-reboxetine) component and the second reboxetine (including S,S-reboxetine)
component,
can be adjusted by using a material that dissolves or disintegrates more or
less slowly in the
digestive system, adjusting the thickness of the coating layer or the coating
material (e.g. a
thicker layer would provide a longer time), and/or by using materials whose
properties are
sensitive to pH. For example, materials that are less stable to, or more
soluble in, acidic pHs,
may dissolve or disintegrate more quickly in the stomach because the stomach
pH is lower
than the pH in the intestines. Conversely, materials that are stable at low
pH, but less stable
at higher pH may dissolve or disintegrate later because of the time it takes
the dosage form
to travel through the gastrointestinal tract.
A controlled release formulation containing reboxetine (including S,S-
reboxetine) can
be coated with one or more functional or non-functional coatings. Examples of
functional
coatings include controlled release polymeric coatings (i.e. controlled
release coats), moisture
barrier coatings, enteric polymeric coatings, and the like.
A controlled release polymer may be used for both sustained release or for
delayed
release, depending upon the structure of the dosage form. For example,
interspersing the
reboxetine (including S,S-reboxetine) throughout a controlled release polymer
can provide
sustained release, since the drug will be released for as long as the polymer
is present in the
GI tract. Delayed release may be achieved by creating a barrier, such as a
coating, which is
intended to last for a shorter time (e.g. less than 12 hours, less than 10
hours, less than 6
hours, less than 3 hours, etc.), so that when the barrier is penetrated, the
reboxetine
(including S,S-reboxetine) is freely released. The thickness of the barrier
can be used to
control the delay time.
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Any suitable controlled release polymer may be used, such as acrylic acid and
nnethacrylic acid copolymers and various esters thereof, e.g. methyl
nnethacrylate
copolymers, ethoxyethyl nnethacrylates, cyanoethyl nnethacrylate, anninoalkyl
nnethacrylate
copolymer, poly(acrylic acid), poly(nnethacrylic acid), nnethacrylic acid
alkylannine copolymer,
poly(nnethyl nnethacrylate), poly(nnethacrylic acid) (anhydride),
polyacrylannide,
poly(nnethacrylic acid anhydride), and glycidyl nnethacrylate copolymers.
Other suitable controlled release polymers include polynnerizable quaternary
ammonium compounds, e.g. quaternized anninoalkyl esters and anninoalkyl amides
of acrylic
acid and nnethacrylic acid, for example p-
nnethacryloxyethyltrinnethylannnnoniunn
nnethosulfate, p-acryloxypropyltrinnethylannnnoniunn chloride,
and
trinnethylanninonnethylnnethacrylannide nnethosulfate. The quaternary ammonium
atom can
also be part of a heterocycle, as in nnethacryloxyethylnnethylnnorpholiniunn
chloride or the
corresponding piperidiniunn salt, or it can be joined to an acrylic acid group
or a nnethacrylic
acid group by way of a group containing hetero atoms, such as a polyglycol
ether group.
Further suitable polynnerizable quaternary ammonium compounds include
quaternized vinyl-
substituted nitrogen heterocycles such as methyl-vinyl pyridiniunn salts,
vinyl esters of
quaternized amino carboxylic acids, styryltrialkyl ammonium salts, and the
like. Other
polynnerizable quaternary ammonium compounds
include
benzyldinnethylannnnoniunnethylnnethacrylate
chloride, diethylnnethylannnnoniunnethyl-
acrylate and -nnethacrylate nnethosulfate, N-
trinnethylannnnoniunnpropylnnethacrylannide
chloride, and N-trinnethylannnnoniunn-2,2-dinnethylpropy1-1-nnethacrylate
chloride.
Delayed release may also be achieved by using a controlled release polymer
that
targets a particular pH, with the understanding that, with proper fasting or
feeding, the
particular pH could correspond to a particular time after administration.
For some controlled release polymers, an acrylic or nnethacrylic polymer
comprises
one or more annnnonio nnethacrylate copolymers. Annnnonio nnethacrylate
copolymers (such
as those sold by Evonik under the trademark EUDRAGIT RS and RL) are fully
polymerized
copolymers of acrylic and nnethacrylic acid esters with a low content of
quaternary
ammonium groups. The ammonium groups are appended to the ester portion of the
nnethacrylate (as 2-trinnethylannnnoniunn-ethyl esters). The charged ammonium
groups in
these polymers make them insoluble and highly permeable with pH-independent
swelling.
These properties make these polymers useful for customized, time-controlled
release of the
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coated drug. In order to obtain a desirable dissolution profile for a given
therapeutically
active agent, such as reboxetine (including S,S-reboxetine), two or more
annnnonio
nnethacrylate copolymers having differing physical properties can be
incorporated. For
example, it is known that by changing the molar ratio of the pre-polymerized
materials
containing quaternary ammonium groups to pre-polymerized materials containing
the
uncharged, neutral nnethacrylic or acrylic esters, the permeability properties
of the resultant
coating can be modified.
In other embodiments, the control releasing coat further includes a polymer
whose
permeability is pH dependent, such as anionic polymers synthesized from
nnethacrylic acid
and nnethacrylic acid methyl ester. Such polymers are commercially available,
e.g., from
Evonik, under the tradenanne EUDRAGIT L and EUDRAGIT S. The ratio of free
carboxyl
groups to the esters is known to be 1:1 in EUDRAGIT Land 1:2 in EUDRAGIT S.
EUDRAGIT
L is insoluble in acids and pure water but becomes increasingly permeable
above pH 5Ø This
makes EUDRAGIT L appropriate for targeting release of the coated drug
substance such as
coated reboxetine (including 5,5-reboxetine) in the duodenum and the jejunum
of the small
intestine. Thus, a EUDRAGIT L coated drug substance may achieve a delay in
maximum
plasma concentration, relative to an uncoated or immediate release drug
substance (e.g.
reboxetine (including 5,5-reboxetine) in a first release component), of about
30 min to about
1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3
hours, or about
3.5-4 hours.
EUDRAGIT S is similar to EUDRAGIT L, except that it becomes increasingly
permeable above pH 7. This makes EUDRAGIT S appropriate for targeting release
of the
coated drug substance such as coated reboxetine (including 5,5-reboxetine) in
the ileum of
the small intestine and also the colon. Thus, a EUDRAGIT S coated drug
substance may
achieve a delay in maximum plasma concentration, relative to an uncoated or
immediate
release drug substance (e.g. reboxetine (including 5,5-reboxetine) in a first
release
component), of about 1-2 hours, about 2-3 hours, about 3-4 hours about 4-5
hours, about 5-
6 hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10
hours.
A hydrophobic acrylic polymer coating can also include a polymer which is
based on
dinnethylanninoethyl nnethacrylate and neutral nnethacrylic acid esters (such
as EUDRAGIT E,
commercially available from Evonik). EUDRAGIT E is not soluble in saliva
(making it useful
for taste and odor masking) but is soluble in gastric fluid with pH 5 or less,
which provides an
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immediate release of drug product in the stomach. Reboxetine (including S,S-
reboxetine)
surrounded with a EUDRAGIT E coating may release reboxetine (including S,S-
reboxetine),
may begin releasing reboxetine (including S,S-reboxetine), or may reach a
first local maximum
in the plasma concentration of reboxetine (including S,S-reboxetine), at a
time of about 0-30
minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after the dosage form
is orally
administered, or any time period in a range bounded by any of these values.
A hydrophobic acrylic polymer coating can include a neutral copolymer based on
a
poly nnethacrylate, such as EUDRAGIT NE (NE=neutral ester), commercially
available from
Evonik. EUDRAGIT NE 30D lacquer films are insoluble in water and digestive
fluids, but
permeable and swellable, providing another option for time-controlled release.
EUDRAGIT
NE has a pH-independent sustained release effect that can release a drug
substance such as
reboxetine (including S,S-reboxetine) over a period of time, or may delay
release for a period
of time, wherein the time of release or delay is about 1-24 hours, about 1-18
hours, about 1-
12 hours, about 1-8 hours, or about 1-6 hours.
In some embodiments, the control releasing coat comprises a polymer comprising
ethyl acrylate and methyl nnethacrylate in a 2:1 ratio (KOLLICOAT EMM 30 D,
BASF).
KOLLICOAT EMM 30 D has a pH-independent sustained release effect that can
release a drug
substance such as reboxetine (including S,S-reboxetine) over a period of time,
or may delay
release for a period of time, wherein the time of release or delay is about 1-
24 hours, about
1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.
In some embodiments, the control releasing coat comprises a polyvinyl acetate
stabilized with polyvinylpyrrolidone and sodium lauryl sulfate such as
KOLLICOAT SR3OD
(BASF). The dissolution profile can be altered by changing the relative
amounts of different
acrylic resin lacquers included in the coating. Also, by changing the molar
ratio of
polynnerizable permeability-enhancing agent (e.g., the quaternary ammonium
compounds)
to the neutral nnethacrylic esters, the permeability properties (which affect
the dissolution
profile) of the resultant coating can be modified. KOLLICOAT SR3OD is another
coating with
a pH-independent sustained release effect that can release a drug substance
such as
reboxetine (including S,S-reboxetine) over a period of time, or may delay
release for a period
of time, wherein the time of release or delay is about 1-24 hours, about 1-18
hours, about 1-
12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2
hours.
In some embodiments, the control releasing coat comprises ethylcellulose,
which can
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be used as a dry polymer (such as ETHOCELTM, Dow Chemical Company) solubilized
in organic
solvent prior to use, or as an aqueous dispersion. One suitable commercially-
available
aqueous dispersion of ethylcellulose is Aquacoat (Danisco). Aquacoat ECD
(ethylcellulose
aqueous dispersion), Aquacoat ARC (alcohol-resistant ethylcellulose aqueous
dispersion),
.. and Aquacoat CPD (cellulose acetate phthalate aqueous dispersion) are all
commercially
available controlled release coatings. Another suitable aqueous dispersion of
ethylcellulose
is commercially available as Surelease (Colorcon, Inc.). This product can be
prepared by
incorporating plasticizer into the dispersion during the manufacturing
process. A hot melt of
a polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleic
acid) may be mixed and
prepared as a homogeneous mixture, which is then diluted with an alkaline
solution to obtain
an aqueous dispersion which can be applied directly onto substrates. These
coatings have a
pH-independent sustained release effect that can release a drug substance such
as reboxetine
(including S,S-reboxetine) over a period of time, or may delay release for a
period of time,
wherein the time of release or delay is about 1-24 hours, about 1-18 hours,
about 1-12 hours,
about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.
Other examples of polymers that can be used in the control-releasing coat
include
cellulose acetate phthalate, cellulose acetate trinnaleate, hydroxypropyl
nnethylcellulose
phthalate, hydroxypropyl nnethylcellulose acetate succinate, polyvinyl alcohol
phthalate,
shellac, hydrogels and gel-forming materials, such as carboxyvinyl polymers,
sodium alginate,
sodium carnnellose, calcium carnnellose, sodium carboxynnethyl starch, poly
vinyl alcohol,
hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch,
and cellulose based
cross-linked polymers in which the degree of crosslinking is low so as to
facilitate adsorption
of water and expansion of the polymer matrix, hydroxypropyl cellulose,
hydroxypropyl
nnethylcellulose, polyvinylpyrrolidone, crosslinked starch, nnicrocrystalline
cellulose, chitin,
pullulan, collagen, casein, agar, gum arabic, sodium carboxynnethyl cellulose,
(swellable
hydrophilic polymers) poly(hydroxyalkyl nnethacrylate) (molecular weight 5 k
to 5000 k),
polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic and cationic
hydrogels, zein,
polyannides, polyvinyl alcohol having a low acetate residual, a swellable
mixture of agar and
carboxynnethyl cellulose, copolymers of nnaleic anhydride and styrene,
ethylene, propylene
or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such
as agar, acacia,
karaya, tragacanth, algins and guar, polyacrylannides, POLYOX polyethylene
oxides
(molecular weight 100 k to 5000 k, Dow), AQUA KEEP acrylate polymers
(composed of mainly
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acrylic acid polymer, sodium salt), diesters of polyglucan, crosslinked
polyvinyl alcohol and
poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides,
methyl cellulose,
sodium or calcium carboxynnethyl cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl
cellulose, hydroxyethyl cellulose, nitro cellulose, carboxynnethyl cellulose,
cellulose ethers,
methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate,
cellulose butyrate,
cellulose propionate, gelatin, starch, nnaltodextrin, pullulan, polyvinyl
pyrrolidone, polyvinyl
alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylannide,
polyacrylic acid, natural
gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium,
potassium alginates,
propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean,
tragacanth,
carrageenan, guar, xanthan, scleroglucan and mixtures and blends thereof.
In some embodiments, the dosage forms of reboxetine (including S,S-reboxetine)
are
coated with polymers in order to facilitate nnucoadhesion within the
gastrointestinal tract.
Non-limiting examples of polymers that can be used for nnucoadhesion include
carboxynnethylcellulose, polyacrylic acid, CarbopolTM (Lubrizol),
polycarbophil, gelatin and
other natural or synthetic polymers.
The polymeric coatings of the present disclosure may be any one of the
described
coatings or may be a combination of two or more of the described coatings to
achieve the
desired release profiles of the release of reboxetine (including S,S-
reboxetine).
In addition to the modified release dosage forms described herein, other
modified
release technologies known to those skilled in the art can be used in order to
achieve the
modified release formulations of the present disclosure, i.e., formulations
which provide a
mean Tmax of the drug and/or other pharnnacokinetic parameters described
herein when
administered e.g., orally or by other mode of administration to human
patients. Such
formulations can be manufactured as a modified release oral formulation in a
suitable tablet
or nnultiparticulate formulation known to those skilled in the art. In either
case, the modified
release dosage form can optionally include a controlled release carrier which
is incorporated
into a matrix along with the drug, or which is applied as a controlled release
coating.
Any dosage form comprising an effective amount of reboxetine (including S,S-
reboxetine) may further comprise a binder, a lubricant, and other conventional
inert
excipients.
A binder (also sometimes called adhesive) can be added to a drug-filler
mixture to
increase the mechanical strength of the granules and tablets during formation.
Binders can
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be added to the formulation in different ways: (1) as a dry powder, which is
mixed with other
ingredients before wet agglomeration, (2) as a solution, which is used as
agglomeration liquid
during wet agglomeration, and is referred to as a solution binder, and (3) as
a dry powder,
which is mixed with the other ingredients before compaction. In this form the
binder is
referred to as a dry binder. Solution binders are a common way of
incorporating a binder into
granules. In certain embodiments, the binder used in the tablets is in the
form of a solution
binder. Non-limiting examples of binders useful include hydrogenated vegetable
oil, castor
oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain
fatty acids, fatty acid
esters, wax-like materials such as fatty alcohols, fatty acid esters, fatty
acid glycerides,
hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol,
hydrophobic
and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof.
Specific
examples of water-soluble polymer binders include modified starch, gelatin,
polyvinylpyrrolidone, cellulose derivatives (e.g. hydroxypropyl
nnethylcellulose (HPMC) and
hydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof. Any
suitable amount
of binder may be present, such as about 0.5-5%, about 5-10%, about 10-15%,
about 15-20%,
about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or about 3% by weight
of the
tablet dry weight. In some embodiments, the binder is polyvinyl alcohol.
Lubricants can be added to pharmaceutical formulations to decrease any
friction that
occurs between the solid and the die wall during tablet manufacturing. High
friction during
tableting can cause a series of problems, including inadequate tablet quality
(capping or even
fragmentation of tablets during ejection, and vertical scratches on tablet
edges) and may even
stop production. Accordingly, lubricants may be added to tablet formulations.
Non-limiting
examples of lubricants useful include glyceryl behenate, stearic acid,
hydrogenated vegetable
oils (such as hydrogenated cottonseed oil (STEROTEX , hydrogenated soybean oil
(STEROTEX HM) and hydrogenated soybean oil & castor wax (STEROTEX K),
stearyl alcohol,
leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium
stearate,
glyceryl nnonostearate, stearic acid, polyethylene glycol, ethylene oxide
polymers (for
example, available under the registered trademark CARBOWAX from Union
Carbide, Inc.,
Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium
oleate, sodium
stearyl funnarate, DL-leucine, colloidal silica, mixtures thereof and others
as known in the art.
In some embodiments, the lubricant is glyceryl behenate (for example,
COMPRITOL 888).
Any suitable amount of binder may be present, such as about 0.5-5%, about 5-
10%, about 10-
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15%, about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or
about 3%
by weight of the tablet dry weight.
In some embodiments, reboxetine (including S,S-reboxetine) is administered
once a
day or twice a day for at least about 3 weeks, at least about 4 weeks, at
least about 5 weeks,
at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at
least about 9 weeks,
at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at
least about 4
months, at least about 5 months, at least about 6 months, at least about 7
months, at least
about 8 months, at least about 9 months, at least about 10 months, at least
about 11 months,
at least about 12 months, at least 1.5 years, at least 2 years, at least about
3 years, at least
about 4 years, at least about 5 years, about 0.1-5 years, about 5-10 years, at
least about 10
years, about 10-15 years, at least about 15 years, about 15-20 years, at least
about 20 years,
or longer. In some embodiments, reboxetine (including S,S-reboxetine) is
administered for
up to about 6 months, up to about 1 year, up to about 2 years, up to about 5
years, up to
about 10 years, up to about 20 years, up to about 40 years, up to about 60
years, or up to
about 90 years.
An example, not as an attempt to limit the scope of the disclosure, of a
useful
composition for a dosage form containing about 5-10 mg of reboxetine
(including S,S-
reboxetine) is shown in Table 1 below:
Table 1. Example of dosage form of reboxetine
Component Amount (wt/wt)
Reboxetine or S,S-reboxetine 30-70%
lubricant 1-10%
diluent 20-70%
disintegrant 1-10%
Treatment of narcolepsy with cataplexy with reboxetine (including S,S-
reboxetine) in
the dosage forms described herein may not have significant side effects as the
existing
treatment options. Treatment of narcolepsy with cataplexy with reboxetine
(including S,S-
reboxetine) in the dosage forms described herein may be well tolerated in
mammals such as
human beings.
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Some embodiments include a kit comprising a pharmaceutical composition
comprising one or more units of a dosage form (e.g. about 1-30, about 30-60,
about 60-90,
about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage
form),
wherein a unit of the dosage form comprises about 0.1-5 mg of reboxetine
(including S,S-
.. reboxetine) and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being.
Some embodiments include a kit comprising a pharmaceutical composition
comprising one or more units of a dosage form (e.g. about 1-30, about 30-60,
about 60-90,
about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage
form),
wherein a unit of the dosage form comprises about 5-10 mg of reboxetine
(including S,S-
reboxetine) and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being.
Some embodiments include a kit comprising a pharmaceutical composition
comprising one or more units of a dosage form (e.g. about 1-30, about 30-60,
about 60-90,
about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage
form),
wherein a unit of the dosage form comprises about 10-15 mg of reboxetine
(including S,S-
reboxetine) and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being.
Some embodiments include a kit comprising a pharmaceutical composition
comprising one or more units of a dosage form (e.g. about 1-30, about 30-60,
about 60-90,
about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage
form),
wherein a unit of the dosage form comprises about 15-20 mg of reboxetine
(including S,S-
reboxetine) and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being.
Some embodiments include a kit comprising a pharmaceutical composition
comprising one or more units of a dosage form (e.g. about 1-30, about 30-60,
about 60-90,
about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage
form),
wherein a unit of the dosage form comprises about 5-20 mg of reboxetine
(including S,S-
reboxetine) and instructions to use the pharmaceutical composition to treat
narcolepsy with
cataplexy in a human being.
The following embodiments are specifically contemplated.
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Embodiment 1. A
method of treating narcolepsy with cataplexy, comprising
administering reboxetine to a human being in need thereof, wherein reboxetine
is
administered at least once daily for more than two weeks, wherein, two weeks
from the
beginning of treatment, the human being experiences a reduction in the number
of cataplexy
attacks in a week, a reduction in the Epworth Sleepiness Scale score, a
decrease in the
cataplexy subscore on the Ullanlinna Narcolepsy Scale (NUS), or a reduction in
the
Maintenance of Wakefulness Test score as a result of the treatment.
Embodiment 2. Use
of reboxetine in the manufacture of a medicament for the
treatment of narcolepsy with cataplexy, wherein reboxetine is administered at
least once
daily for at least three weeks.
Embodiment 3. A
kit comprising a pharmaceutical composition comprising reboxetine
and instructions to use the pharmaceutical composition to treat narcolepsy
with cataplexy in
a human being, wherein reboxetine is administered at least once daily for at
least three
weeks.
Embodiment 4. The method, the use, or the kit of embodiment 1, 2, or 3,
wherein
reboxetine is administered twice daily, wherein a first dosage form is
administered in the
morning and a second dosage form is administered about 2 hours to about 6
hours later.
Embodiment 5. The
method, the use, or the kit of embodiment 4, wherein the second
dosage form is administered about 2 hours to about 3 hours after the first
dosage form.
Embodiment 6. The method, the use, or the kit of embodiment 4, wherein the
second
dose is administered about 3 hours to about 4 hours after the first dosage
form.
Embodiment 7. The
method, the use, or the kit of embodiment 4, wherein the second
dosage form is administered about 4 hours to about 5 hours after the first
dosage form.
Embodiment 8. The
method, the use, or the kit of embodiment 4, wherein the second
dosage form is administered about 5 hours to about 6 hours after the first
dosage form.
Embodiment 9. The
method, the use, or the kit of embodiment 1, wherein a single
dosage form is administered daily, wherein the single dosage form contains a
first release
component comprising reboxetine and a second release component comprising
reboxetine,
wherein the first release component provides a first local maximum in the
plasma
concentration of reboxetine and the second release component provides a second
local
maximum in the plasma concentration of reboxetine, wherein the first local
maximum in the
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plasma concentration of reboxetine occurs about 2 to about 6 hours before the
second local
maximum in the plasma concentration of reboxetine.
Embodiment 10. The
method, the use, or the kit of embodiment 9, wherein the second
local maximum in the plasma concentration of reboxetine occurs about 2 to
about 3 hours
after the first local maximum in the plasma concentration of reboxetine.
Embodiment 11. The
method, the use, or the kit of embodiment 9, wherein the second
local maximum in the plasma concentration of reboxetine occurs about 3 to
about 4 hours
after the first local maximum in the plasma concentration of reboxetine.
Embodiment 12. The
method, the use, or the kit of embodiment 9, wherein the second
local maximum in the plasma concentration of reboxetine occurs about 4 to
about 5 hours
after the first local maximum in the plasma concentration of reboxetine.
Embodiment 13. The
method, the use, or the kit of embodiment 9, wherein the second
local maximum in the plasma concentration of reboxetine occurs about 5 to
about 6 hours
after the first local maximum in the plasma concentration of reboxetine.
Embodiment 14. The method, the use, or the kit of embodiment 1, 2, 3, 4, 5,
6, 7, 8, 9,
10, or 11, 12, or 13, wherein the human being is selected for not suffering
from depression.
Embodiment 15. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, or 14, the dose amount of reboxetine is increased for 1 to 7
days, and then
maintained constant at a total daily dose of about 0.006 nnnnol to about 0.01
nnnnol.
Embodiment 16. The method, the use, or the kit of embodiment 1, 2, 3, 4, 5,
6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose amount of reboxetine is increased
for 1 to 7 days,
and then maintained constant at a total daily dose of about 0.01 nnnnol to
about 0.02 nnnnol.
Embodiment 17. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.02 nnnnol to about 0.03
nnnnol.
Embodiment 18. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.03 nnnnol to about 0.04
nnnnol.
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Embodiment 19. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.04 nnnnol to about 0.05
nnnnol.
Embodiment 20. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.05 nnnnol to about 0.06
nnnnol.
Embodiment 21. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.06 nnnnol to about 0.07
nnnnol.
Embodiment 22. The method, the use, or the kit of embodiment 1, 2, 3, 4, 5,
6, 7, 8, 9,
10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1
to 7 days, and then
maintained constant at a total daily dose of about 0.07 nnnnol to about 0.08
nnnnol.
Embodiment 23. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the reboxetine
is in a dosage form
and the dosage form contains about 5 mg of reboxetine.
Embodiment 24. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the reboxetine
is in a dosage form
and the dosage form contains about 10 mg of reboxetine.
Embodiment 25. The
method, the use, or the kit of embodiment 23, wherein the dosage
form is administered once daily or twice daily for at least three weeks.
Embodiment 26. The
method, the use, or the kit of embodiment 24, wherein the dosage
form is administered once daily or twice daily for at least three weeks.
Embodiment 27. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein
the human being
experiences an increase in sleep latency on the multiple sleep latency test
(MSLT).
Embodiment 28. The
method, the use, or the kit of embodiment 27, wherein the human
being experiences an increase of at least 10% in sleep latency on the MSLT.
Embodiment 29. The
method, the use, or the kit of embodiment 27, wherein the human
being experiences an increase of at least 20% in sleep latency on the MSLT.
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Embodiment 30. The
method, the use, or the kit of embodiment 27, wherein the human
being experiences an increase of at least 30% in sleep latency on the MSLT.
Embodiment 31. The
method, the use, or the kit of embodiment 27, wherein the human
being experiences an increase of at least 40% in sleep latency on the MSLT.
Embodiment 32. The method, the use, or the kit of embodiment 27, wherein
the human
being experiences an increase of at least 50% in sleep latency on the MSLT.
Embodiment 33. The
method, the use, or the kit of embodiment 27, wherein the human
being experiences an increase of at least 60% in sleep latency on the MSLT.
Embodiment 34. The
method, the use, or the kit of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, or 33,
wherein the human being experiences a decrease of at least 15% in the
cataplexy subscore
on the UNS.
Embodiment 35. The
method, the use, or the kit of embodiment 34, wherein the human
being experiences a decrease of at least 20% in the cataplexy subscore on the
UNS.
Embodiment 36. The method, the use, or the kit of embodiment 34, wherein
the human
being experiences a decrease of at least 30% in the cataplexy subscore on the
UNS.
Embodiment 37. The
method, the use, or the kit of embodiment 34, wherein the human
being experiences a decrease of at least 40% in the cataplexy subscore on the
UNS.
Embodiment 38. The
method, the use, or the kit of embodiment 34, wherein the human
being experiences a decrease of at least 50% in the cataplexy subscore on the
UNS.
Embodiment 39. The
method, the use, or the kit of embodiment 34, wherein the human
being experiences a decrease of at least 60% in the cataplexy subscore on the
UNS.
Embodiment 40. The
method, the use, or the kit of embodiment 34, wherein the human
being experiences a decrease of at least 70% in the cataplexy subscore on the
UNS.
Embodiment 41. The method, the use, or the kit of embodiment 34, wherein
the human
being has a cataplexy subscore of about 0.
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Embodiment 42. A
method of improving the ability to concentrate in a human being
suffering from narcolepsy, comprising administering reboxetine to a human
being in need
thereof.
Embodiment 43. The
method of embodiment 42, wherein the human being is selected
for being in need of improvement in ability to concentrate or for having
difficulty
concentrating.
Embodiment 44. The
method of embodiment 42 or 43, wherein, as compared to before
any reboxetine is administered, the human being has an improvement in the
Ability to
Concentrate item of the NSAQ that is at least about -0.1.
Embodiment 45. A method of treating fibronnyalgia, comprising administering
esreboxetine to a human being in need thereof, wherein a daily dose of about 1
mg to about
2 mg of esreboxetine is administered for at least six weeks, wherein the human
being
experiences a reduction in fibronnyalgia pain during the course of the
treatment, as measured
by a visual analog scale (VAS) score, that is greater than the reduction in
pain that the human
being would have experienced by administering a placebo.
Embodiment 46. The
method of embodiment 45, wherein about 1 mg to about 2 mg of
esreboxetine is administered once a day.
Embodiment 47. The
method of embodiment 45, wherein about 0.5 mg to about 1 mg
of esreboxetine is administered twice a day.
Embodiment 48. The method of embodiment 45, 46, or 47, wherein the human
being is
selected for having a Global Fatigue Index score of at least about 8.
Embodiment 49. The
method of embodiment 45, 46, 47, or 48, wherein after
esreboxetine is administered daily for six weeks, the VAS score of the
fibronnyalgia pain of the
human being is reduced by at least 20% as compared to the VAS score of the
fibronnyalgia
pain of the human being immediately prior to administering the first dose of
esreboxetine.
Embodiment 50. The
method of embodiment 45, 46, 47, 48, or 49, wherein after
esreboxetine is administered daily for six weeks, the VAS score of the
fibronnyalgia pain of the
human being is reduced by at least 50% as compared to the VAS score of the
fibronnyalgia
pain of the human being immediately prior to administering the first dose of
esreboxetine.
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Embodiment 51. A
method of treating fibronnyalgia, comprising administering
esreboxetine to a human being in need thereof, wherein a daily dose of about 2
mg to about
4 mg of esreboxetine is administered for at least six weeks, wherein the human
being
experiences a reduction in pain during the course of the treatment, as
measured by a visual
analog scale (VAS) score, that is greater than the reduction in pain that the
human being
would have experienced by administering a placebo.
Embodiment 52. The
method of embodiment 51, wherein about 1 mg to about 2 mg of
esreboxetine is administered once a day.
Embodiment 53. The
method of embodiment 51, wherein about 0.5 mg to about 1 mg
of esreboxetine is administered twice a day.
Embodiment 54. The
method of embodiment 51, 52, or 53, wherein the human being is
selected for having a Global Fatigue Index score of at least about 8.
Embodiment 55. The
method of embodiment 51, 52, 53, or 54, wherein after
esreboxetine is administered daily for six weeks, the VAS score of the
fibronnyalgia pain of the
human being is reduced by at least 20% as compared to the VAS score of the
fibronnyalgia
pain of the human being immediately prior to administering the first dose of
esreboxetine.
Embodiment 56. The
method of embodiment 51, 52, 53, 54, or 55, wherein after
esreboxetine is administered daily for six weeks, the VAS score of the
fibronnyalgia pain of the
human being is reduced by at least 50% as compared to the VAS score of the
fibronnyalgia
pain of the human being immediately prior to administering the first dose of
esreboxetine.
Embodiment 57. A
method of treating fibronnyalgia, comprising administering
esreboxetine to a human being in need thereof, wherein a daily dose of about
0.5 mg to about
1 mg of esreboxetine is administered for at least six weeks, wherein the human
being
experiences a reduction in pain during the course of the treatment, as
measured by a visual
analog scale (VAS) score, that is greater than the reduction in pain that the
human being
would have experienced by administering a placebo.
Embodiment 58. The
method of embodiment 57, wherein about 1 mg to about 2 mg of
esreboxetine is administered once a day.
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Embodiment 59. The
method of embodiment 57, wherein about 0.5 mg to about 1 mg
of esreboxetine is administered twice a day.
Embodiment 60. The
method of embodiment 57, 58, or 59, wherein the human being is
selected for having a Global Fatigue Index score of at least about 8.
Embodiment 61. The method of embodiment 57, 58, 59, or 60, wherein after
esreboxetine is administered daily for six weeks, the VAS score of the
fibronnyalgia pain of the
human being is reduced by at least 20% as compared to the VAS score of the
fibronnyalgia
pain of the human being immediately prior to administering the first dose of
esreboxetine.
Embodiment 62. The
method of embodiment 61, wherein after esreboxetine is
administered daily for six weeks, the VAS score of the fibronnyalgia pain of
the human being
is reduced by at least 50% as compared to the VAS score of the fibronnyalgia
pain of the human
being immediately prior to administering the first dose of esreboxetine.
EXAMPLES
Example 1
A 40 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the number of cataplexy attacks have decreased by 10-30%.
Example 2
A 20 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the number of cataplexy attacks have decreased by 30-60%.
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Example 3
A 60 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
.. the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the number of cataplexy attacks have decreased by 60-100%.
Example 4
A 50 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the ESS score has decreased by 10-30%.
Example 5
A 25 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the ESS score has decreased by 30-60%.
Example 6
A 47 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
.. 1 pm for three weeks. The patient is evaluated prior to treatment, and
weekly to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the ESS score has decreased by 60-100%.
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Example 7
A 19 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the MWT score has decreased by 10-30%.
Example 8
A 42 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the MWT score has decreased by 30-60%.
Example 9
A 33 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After one
week of
treatment, the MWT score has decreased by 60-100%.
Example 10
A 54 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the number of cataplexy attacks have decreased by 10-30%.
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Example 11
A 27 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the number of cataplexy attacks have decreased by 30-60%.
Example 12
A 52 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the number of cataplexy attacks have decreased by 60-100%.
Example 13
A 66 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the ESS score has decreased by 10-30%.
Example 14
A 34 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the ESS score has decreased by 30-60%.
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Example 15
A 35 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the ESS score has decreased by 60-100%.
Example 16
A 19 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
.. given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg
of reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the MWT score has decreased by 10-30%.
Example 17
A 70 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
.. score, the NSAQ score, and the ability to concentrate on the NSAQ. After
three weeks of
treatment, the MWT score has decreased by 30-60%.
Example 18
A 57 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the MWT score has decreased by 60-100%.
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Example 19
A 20 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the HAM-D score has decreased by 10-30%.
Example 20
A 69 year old male is diagnosed as suffering from narcolepsy with cataplexy.
He is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the HAM-D score has decreased by 30-60%.
Example 21
A 56 year old female is diagnosed as suffering from narcolepsy with cataplexy.
She is
given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of
reboxetine at
1 pm for three weeks. The patient is evaluated prior to treatment, and weekly
to determine
the MWT score, the number of cataplexy attacks, the PGI-C score, the HAM-D
score, the ESS
score, the NSAQ score, and the ability to concentrate on the NSAQ. After three
weeks of
treatment, the HAM-D score has decreased by 60-100%.
Example 22
A Phase 2, double-blind, randomized, placebo-controlled, crossover,
multicenter trial
of reboxetine was carried out in patients with narcolepsy. A total of 21
patients with a
diagnosis of narcolepsy with cataplexy were treated for 2 weeks with
reboxetine or with
placebo, followed by a crossover to the other treatment after a 1-week down-
titration and
washout period. Reboxetine was administered orally twice daily, with a total
daily dose of 8
mg for Week 1 which was escalated to 10 mg for Week 2. Patients were
randomized in a 1:1
ratio either to treatment with reboxetine followed by placebo (sequence 1), or
to treatment
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with placebo followed by reboxetine (sequence 2). The average number of
cataplexy attacks
at baseline was 30. Key assessments were made daily using an electronic diary.
The
prespecified primary endpoint was the change in the weekly number of cataplexy
attacks,
averaged over the 2-week treatment period (overall treatment effect).
Secondary endpoints
included changes in the number of inadvertent naps, cognition, and Epworth
Sleepiness Scale.
Cognition was assessed using the Ability to Concentrate item of the Narcolepsy
Symptom
Assessment Questionnaire, a patient reported outcome measure. This item is
rated on 5-
point scale (1=very good to 5=very poor). All analyses were conducted on an
intent-to-treat
basis.
As shown in FIG. 1, Reboxetine met the prespecified primary endpoint by
demonstrating a highly statistically significant reduction from baseline in
the mean weekly
number of cataplexy attacks, averaged for the 2-week treatment period (overall
treatment
effect), as compared to placebo (p<0.001). At Week 2, reboxetine demonstrated
a mean
reduction of 14.6 cataplexy attacks per week compared to a reduction of 2.6
attacks per week
for placebo (p=0.002), representing mean reductions of 48.7% and 8.7% from
baseline,
respectively (FIG. 1). Furthermore, Reboxetine treatment resulted in rapid
reduction in the
cataplexy attacks. After 1-week treatment, reboxetine demonstrated a mean
reduction of
13.0 cataplexy attacks compared to a reduction of 0.3 attacks for placebo
(p<0.001),
representing mean reductions of 43.3% and 1.0% from baseline, respectively
(FIG. 1). The
proportion of patients achieving a 50% or greater reduction in the weekly
number of
cataplexy attacks was 76.2% for reboxetine, compared to 30.0% for placebo
(p=0.003) at
Week 2 (FIG. 2). The proportion of patients achieving a 75% or greater
reduction in the weekly
number of cataplexy attacks was 42.9% for reboxetine, compared to 10.0% for
placebo
(p=0.018) at Week 2 (FIG. 3). The improvement in cataplexy was rapid with
reboxetine
demonstrating significant benefit over placebo as early as Week 1 (p<0.001).
Reboxetine significantly improved EDS (excessive daytime sleepiness) symptoms
compared to placebo, as measured by the Epworth Sleepiness Scale (ESS) and by
the
frequency of inadvertent naps. As shown in FIG. 4, the improvement on the ESS
with
reboxetine treatment was twice that observed with placebo, with reductions in
the ESS score
.. from baseline of 6.0 and 3.1, respectively for reboxetine and placebo
(p=0.003). Reboxetine
treatment resulted in a 31.8% mean reduction from baseline in the average
weekly number
of inadvertent naps versus a 5.3% mean reduction for placebo (p<0.001) at Week
2 (FIG. 5).
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As shown in FIG. 6, reboxetine treatment resulted in a greater number of
patients with 50%
or greater reduction in inadvertent naps (38.1%) as compared to placebo
(10.0%) (p=0.036).
The improvement in frequency of inadvertent naps was rapid with reboxetine
demonstrating
significant benefit over placebo as early as Week 1.
Reboxetine significantly improved cognitive function compared to placebo over
the 2-
week treatment period as measured by the Ability to Concentrate item of the
Narcolepsy
Symptom Assessment Questionnaire (NSAQ), which was assessed daily (p<0.01)
(FIGs. 7-8).
For this assessment, patients rated their ability to concentrate on a 5-point
scale (1=very
good, 2=good, 3=average, 4=poor, and 5=very poor). At the end of the 2-week
treatment
period, 42.9% of patients had an ability to concentrate that was "good" to
"very good" with
reboxetine treatment, compared to 25.0% of patients with placebo, and 0% of
patients at
baseline. The improvement in the ability to concentrate was rapid with
reboxetine
demonstrating significant improvement over placebo (38.1% vs 15.0%) as early
as Week 1
(p=0.007).
Reboxetine significantly improved sleep quality, as measured by overall
improvement
and by number of awakenings at night, and reduced sleep-related symptoms, as
compared to
placebo. As shown in FIG. 9, reboxetine treatment resulted in 45.0% of
patients reporting
improved sleep quality versus 5.3% of patients with placebo (p=0.007).
Reboxetine treatment
resulted in 30.0% of patients reporting a reduction in the number of
awakenings at night
versus 5.3% of patients with placebo (p=0.044). Reboxetine treatment also
resulted in greater
proportion of patients with reductions in sleep paralysis episodes, and in
hypnagogic
hallucinations, as compared to placebo.
Reboxetine was safe and well tolerated. There were no serious adverse events
reported in the trial, and no discontinuations due to adverse events. The
overall percentage
of patients experiencing adverse events was 42.9% with reboxetine and 40.0%
with placebo,
with the most commonly reported adverse events with reboxetine treatment being
anxiety,
constipation, and insomnia. The completion rate was 91% for patients
randomized to
treatment sequence 1 (reboxetine followed by placebo) and 100% for those
randomized to
sequence 2 (placebo followed by reboxetine).
Unless otherwise indicated, all numbers expressing quantities of ingredients,
properties such as amounts, percentage, and so forth used in the specification
and claims are
to be understood in all instances as indicating both the exact values as shown
and as being
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modified by the term "about." Accordingly, unless indicated to the contrary,
the numerical
parameters set forth in the specification and attached claims are
approximations that may
vary depending upon the desired properties sought to be obtained. At the very
least, and not
as an attempt to limit the application of the doctrine of equivalents to the
scope of the claims,
each numerical parameter should at least be construed in light of the number
of reported
significant digits and by applying ordinary rounding techniques.
The terms "a," "an," "the" and similar referents used in the context of
describing the
embodiments (especially in the context of the following claims) are to be
construed to cover
both the singular and the plural, unless otherwise indicated herein or clearly
contradicted by
context. All methods described herein can be performed in any suitable order
unless
otherwise indicated herein or otherwise clearly contradicted by context. The
use of any and
all examples, or exemplary language (e.g., "such as") provided herein is
intended merely to
better illuminate the embodiments and does not pose a limitation on the scope
of any claim.
No language in the specification should be construed as indicating any non-
claimed element
essential to the practice of the claims.
Groupings of alternative elements or embodiments disclosed herein are not to
be
construed as limitations. Each group member may be referred to and claimed
individually or
in any combination with other members of the group or other elements found
herein. It is
anticipated that one or more members of a group may be included in, or deleted
from, a
group for reasons of convenience and/or to expedite prosecution. When any such
inclusion
or deletion occurs, the specification is deemed to contain the group as
modified thus fulfilling
the written description of all Markush groups if used in the appended claims.
Certain embodiments are described herein, including the best mode known to the
inventors for carrying out the claimed embodiments. Of course, variations on
these described
embodiments will become apparent to those of ordinary skill in the art upon
reading the
foregoing description. The inventor expects skilled artisans to employ such
variations as
appropriate, and the inventors intend for the claimed embodiments to be
practiced otherwise
than specifically described herein. Accordingly, the claims include all
modifications and
equivalents of the subject matter recited in the claims as permitted by
applicable law.
Moreover, any combination of the above-described elements in all possible
variations thereof
is contemplated unless otherwise indicated herein or otherwise clearly
contradicted by
context.
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In closing, it is to be understood that the embodiments disclosed herein are
illustrative
of the principles of the claims. Other modifications that may be employed are
within the
scope of the claims. Thus, by way of example, but not of limitation,
alternative embodiments
may be utilized in accordance with the teachings herein. Accordingly, the
claims are not
limited to embodiments precisely as shown and described.
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