Note: Descriptions are shown in the official language in which they were submitted.
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
USE OF REBOXETINE TO TREAT NARCOLEPSY
Inventor: Herriot Tabuteau
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
62/745,956, filed
October 15, 2018, which is incorporated by reference herein in its 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. The debilitating effects of narcolepsy are far reaching for the
estimated nearly
200,000 patients living with this disorder in the United States. Narcolepsy
interferes with
mental and social functioning, increases work and driving related accidents,
and results in a
nearly two-fold higher mortality rate. 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 DEA scheduling.
SUMMARY
Described herein are methods of treating narcolepsy with cataplexy, comprising
administering reboxetine to a human being in need thereof.
Some embodiments include use of reboxetine in the manufacture of a medicament
for the treatment of narcolepsy with cataplexy.
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.
1
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
In some embodiments, reboxetine is administered at least once daily for at
least three
weeks. In some embodiments, three 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, or a reduction in the Maintenance of
Wakefulness Test
score as a result of the treatment.
DETAILED DESCRIPTION
Reboxetine has the potential to treat the symptoms of narcolepsy along with
its lack
of DEA scheduling 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 reboxetine may have, and/or may be selected for
having,
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,
2
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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 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 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.
Some patients treated with 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 reboxetine may be, and/or may be selected for
being,
young children presenting with excessively long night sleep.
Some patients treated with reboxetine may be, and/or may be selected for
being,
young children presenting with resumption of previously discontinued daytime
napping.
Some patients treated with 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
3
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 reboxetine may have, and/or may be selected for
having,
a score on the Epworth Sleepiness Scale (ESS) that is 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 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.
Some patients treated with 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
reboxetine for
treatment.
4
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
In some embodiments, the patient has, and/or may be selected for having, an
age of
about 0-5 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 reboxetine for treatment.
Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy
and/or EDS)
may be, and/or may be selected for being female.
Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy
and/or EDS)
may be, and/or may be selected for being male.
Some patients treated with 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 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 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
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 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 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
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 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 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 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 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 reboxetine for narcolepsy (e.g. with cataplexy and/or
EDS) may not
5
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
have, and/or may be selected for not having, a seizure disorder. Some patients
treated with
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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
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 reboxetine for
narcolepsy (e.g.
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, an anxiety
6
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
disorder. Some patients treated with 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 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 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 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 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 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
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
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 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 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
treated with 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 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 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 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 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 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
reboxetine for
7
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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 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 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
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
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
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 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 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
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
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 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 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 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 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 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
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 reboxetine for
narcolepsy (e.g.
8
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
with cataplexy and/or EDS) may not have, and/or may be selected for not
having, a
schizotypy. Some patients treated with 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 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
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 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 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 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 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
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
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
treated with
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
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 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 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 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 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 reboxetine for narcolepsy
(e.g. with
9
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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
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 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.
Some patients treated with 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 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 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 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 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
reboxetine for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, an a nnnesia/annnestic syndrome. Some patients treated with 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 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 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
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
reboxetine for
narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be
selected for not
having, a speech disorder. Some patients treated with 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 reboxetine for narcolepsy (e.g. with cataplexy
and/or EDS) may
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
not have, and/or may be selected for not having, Parkinson's disease. Some
patients treated
with 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 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
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
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 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 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 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
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 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 with 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 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 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 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 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 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
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 reboxetine for narcolepsy
(e.g. with
cataplexy and/or EDS) may not have, and/or may be selected for not having, a
cerebral palsy.
11
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
Some patients treated with 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
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
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 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 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 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 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 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 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 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
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 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 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 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 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 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 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
reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
12
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
selected for not having, a mixed dementia. Some patients treated with
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 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 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 reboxetine for narcolepsy
(e.g. with
cataplexy and/or EDS) may not have, and/or may be selected for not having,
Wernicke-
Korsa koff Syndrome.
Some patients treated with 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 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 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
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 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 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 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 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
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 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 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 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
13
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
with 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
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).
Some patients treated with 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 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 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 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 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
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 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 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 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
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 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 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 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 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
14
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
(CADAS ILL Some patients treated with 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 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 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 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 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
reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, a striatonigra I degeneration. Some patients treated
with 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 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 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 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 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 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 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
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
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 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 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 reboxetine for narcolepsy (e.g. with cataplexy
and/or EDS) may
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
not have, and/or may be selected for not having, generalized seizures. Some
patients treated
with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,
and/or may be
selected for not having, generalized tonic-clonic seizures. Some patients
treated with
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 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 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
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 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 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 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
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 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
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 reboxetine for
narcolepsy (e.g. with
cataplexy and/or EDS) may not have, and/or may be selected for not having, a
voice disorder
due to uncontrolled laryngeal muscle spasms. Some patients treated with
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 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 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 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 reboxetine for narcolepsy (e.g. with
cataplexy and/or
16
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
EDS) may not have, and/or may be selected for not having, a diabetic
neuropathy. Some
patients treated with 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 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 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
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
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 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 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
reboxetine for
narcolepsy with cataplexy is, and may be selected for being, a predisposed
individual with
specific genetic markers including human leukocyte antigen (H LA DQB1/06:02)
and/or T-cell
receptor alpha variants. Some patients being treated with reboxetine may not
have, and may
be selected for not having, narcolepsy associated with loss of hypocretin
neurons. Some
patients being treated with reboxetine may have, or may be selected for
having, narcolepsy
precipitated by seasonal Streptococcus infections, H1N1 influenza, and/or H 1N
1 vaccination
in genetically predisposed individuals.
17
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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)
In some embodiments, administering 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 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, a selective serotonin reuptake inhibitor (SSRI),
or a selective
norepinephrine reuptake inhibitor (SNRI)).
In some embodiments, administering 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 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).
In some embodiments, administering reboxetine may reduce the number of
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 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
18
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 14
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-
10 .. 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
control (including an active control, such as a stimulant (e.g.
nnethylphenidate, an
15 amphetamine), nnodafanil, arnnodafanil, sodium oxybate, a tricyclic
antidepressant, an SSRI,
or an SNRI).
In some embodiments, administering reboxetine may reduce the 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
20 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 control
(including an
19
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
active control, such as a stimulant (e.g. nnethylphenidate, an amphetamine),
nnodafanil,
arnnodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN
RI).
In some embodiments, administering reboxetine may reduce the 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
minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5
minutes,
15 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
20
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).
In some embodiments, administering 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 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, about 11, about 2-3, about 3-4,
about 4-5, about
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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).
In some embodiments, administering 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%, about
60-70%, about
70-80%, about 80-90%, about 90-100%, 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
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).
In some embodiments, administering 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
21
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
(e.g. nnethylphenidate, an amphetamine), nnodafanil, arnnodafanil, sodium
oxybate, a tricyclic
antidepressant, an SSRI, or an SNRI).
In some embodiments, administering 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).
In some embodiments, administering 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).
In some embodiments, administering 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).
In some embodiments, administering 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
22
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 SN
RI).
In some embodiments, administering 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 SN
RI).
In some embodiments, administering 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%,
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 SN
RI).
Reboxetine (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.
23
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
0 0-/
0
.
( _____________ NH (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
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 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 may be administered in a manner
that
results in 1) a first local maximum in reboxetine plasma concentration and 2)
a second local
maximum in reboxetine plasma concentration.
There are many potential ways that reboxetine could be administered in a
manner
that results in a first local maximum in reboxetine plasma concentration and a
second local
maximum in 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 in a manner that results in a first
local maximum in
reboxetine plasma concentration and a second local maximum in reboxetine
plasma
concentration is to administer a first dosage form containing reboxetine and,
at a later time,
a second dosage form containing reboxetine. The doses are administered at
times that result
in a first local maximum in reboxetine plasma concentration and a second local
maximum in
24
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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.
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.
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,
may begin releasing reboxetine, or may result in a first local maximum in the
plasma
concentration of 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 after the first release component releases reboxetine, or may cause
an increase
of reboxetine plasma concentration or a second local maximum in the plasma
concentration
of 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 is first released from the first release component, or
after the first local
maximum in the plasma concentration of 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
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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
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 before
the second release component particles release 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
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 occurs less than half a day after the first local
maximum plasma
concentration of 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, 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 plasma concentration in that the first release component releases
the reboxetine
that contributes to the first local maximum in reboxetine plasma
concentration. For example,
the first release component could release reboxetine faster or sooner than the
second release
component, so that most of the reboxetine contributing to the first local
maximum plasma
26
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
concentration of 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 plasma concentration in that the second release component releases
the
reboxetine that contributes to the second local maximum in reboxetine plasma
concentration. For example, the second release component could delay release
of its
reboxetine so that at a time when the reboxetine plasma concentration is
decreasing after
the first local maximum, the second release component releases a sufficient
amount of
reboxetine to again increase the plasma concentration of reboxetine so that
the second local
maximum in reboxetine plasma concentration is achieved.
For dosage forms containing a first release component and a second release
component, any suitable amount of 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 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 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.
The dose of 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
27
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
dose could be a once daily 10 mg 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 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 maintenance dose may be administered for 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 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 first release component provides immediate release of
reboxetine. In some embodiments, the first release component provides delayed
release of
reboxetine. In some embodiments, the first release component provides
sustained release
of reboxetine.
In some embodiments, the second release component provides immediate release
of
reboxetine. In some embodiments, the second release component provides delayed
release
of reboxetine. In some embodiments, the second release component provides
sustained
release of reboxetine.
In some embodiments, the first release component provides immediate release of
reboxetine, and the second release component provides delayed release of
reboxetine. In
some embodiments, the first release component provides immediate release of
reboxetine,
28
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
and the second release component provides sustained release of reboxetine.
With respect to methods wherein the reboxetine is administered in a first
dosage form
containing reboxetine and a second dosage form containing reboxetine, any
suitable amount
of 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 0.021-0.024 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 is administered in a first
dosage form
containing reboxetine and a second dosage form containing reboxetine, any
suitable amount
of 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 provides immediate release of
reboxetine. In some embodiments, the first dosage form provides delayed
release of
reboxetine. In some embodiments, the first dosage form provides sustained
release of
reboxetine.
In some embodiments, the second dosage form provides immediate release of
reboxetine. In some embodiments, the second dosage form provides delayed
release of
reboxetine. In some embodiments, the second dosage form provides sustained
release of
reboxetine.
With respect to single dosage forms containing both a first release component
and a
29
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 to be fully absorbed and/or reach a maximum 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 may also
be affected by the time of the day taken the drug such as 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 is the presence or
absence of
a controlled release coating on the drug such as reboxetine.
Controlled release includes: immediate release of drug substance such as
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.
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 may be achieved by completely or partially
surrounding the
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 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. In some cases, the reboxetine may be
completely
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
released in the duodenum. In some embodiments, the reboxetine may be partially
released
in the duodenum, and partially released in the jejunum. In some cases, the
reboxetine may
be completely released in the jejunum. In some cases, the reboxetine may be
partially
released in the jejunum and partially released in the ilium. In some cases,
the reboxetine may
be completely released in the ilium. In some cases, the reboxetine may be
partially released
in the duodenum, the jejunum, and the ilium. In some embodiments, the
reboxetine may be
partially released in the ilium, and partially released in the colon. In some
cases, the
reboxetine may be completely released in the colon.
The time of the delayed release, e.g. between release of the first reboxetine
component and the second 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 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 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 is freely released. The
thickness of the
barrier can be used to control the delay time.
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
31
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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
coated drug. In order to obtain a desirable dissolution profile for a given
therapeutically
active agent, such as reboxetine, two or more annnnonio nnethacrylate
copolymers having
differing physical properties can be incorporated. For example, it is known
that by changing
32
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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
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 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 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
immediate release of drug product in the stomach. Reboxetine surrounded with a
EUDRAGIT E coating may release reboxetine, may begin releasing reboxetine, or
may reach
a first local maximum in the plasma concentration of 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.
33
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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 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 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
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
34
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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
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
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
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 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.
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 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
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
36
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 (H PC)), 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-
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 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
37
CA 03115983 2021-04-09
WO 2020/081461 PCT/US2019/056134
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.
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 is shown
in Table 1
below:
Table 1. Example of dosage form of reboxetine
Component Amount (wt/wt)
reboxetine 30-70%
lubricant 1-10%
diluent 20-70%
disintegrant 1-10%
Treatment of narcolepsy with cataplexy with 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 in the dosage forms
described herein
may be well tolerated in mammals such as human beings.
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 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 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),
38
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
wherein a unit of the dosage form comprises about 10-15 mg of 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 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 and
instructions to
use the pharmaceutical composition to treat narcolepsy with cataplexy in a
human being.
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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After one
week of
treatment, the number of cataplexy attacks have decreased by 30-60%.
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
39
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
the number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After one
week of
treatment, the ESS score has decreased by 60-100%.
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 number of cataplexy attacks, the ESS score, and the MWT score. After one
week of
treatment, the MWT score has decreased by 10-30%.
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After three
weeks of
treatment, the number of cataplexy attacks have decreased by 10-30%.
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 number of cataplexy attacks, the ESS score, and the MWT score. 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
41
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
the number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After three
weeks of
treatment, the ESS score has decreased by 30-60%.
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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After three
weeks of
treatment, the MWT score has decreased by 10-30%.
42
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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 number of cataplexy attacks, the ESS score, and the MWT score. 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 number of cataplexy attacks, the ESS score, and the MWT score. After three
weeks of
treatment, the MWT score has decreased by 60-100%.
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
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.
43
CA 03115983 2021-04-09
WO 2020/081461
PCT/US2019/056134
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.
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.
44
