U.S. patent application number 17/648046 was filed with the patent office on 2022-05-05 for method of treatment.
The applicant listed for this patent is Vanda Pharmaceuticals Inc.. Invention is credited to Christian Lavedan, Mihael H. Polymeropoulos.
Application Number | 20220133681 17/648046 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220133681 |
Kind Code |
A1 |
Lavedan; Christian ; et
al. |
May 5, 2022 |
METHOD OF TREATMENT
Abstract
Embodiments of the invention relate to the treatment of sleep
disturbances in individuals with Smith-Magenis Syndrome (SMS).
Inventors: |
Lavedan; Christian;
(Potomac, MD) ; Polymeropoulos; Mihael H.;
(Potomac, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vanda Pharmaceuticals Inc. |
Washington |
DC |
US |
|
|
Appl. No.: |
17/648046 |
Filed: |
January 14, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16848150 |
Apr 14, 2020 |
11266622 |
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17648046 |
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16211687 |
Dec 6, 2018 |
10653665 |
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16848150 |
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15326934 |
Jan 17, 2017 |
10179119 |
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PCT/US15/47610 |
Aug 29, 2015 |
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16211687 |
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62044856 |
Sep 2, 2014 |
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62169635 |
Jun 2, 2015 |
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International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 45/06 20060101 A61K045/06; A61K 31/00 20060101
A61K031/00 |
Claims
1. A method of treating a patient suffering from Smith-Magenis
Syndrome (SMS), the method comprising: administering to the patient
tasimelteon in an amount effective to improve sleep in the
patient.
2. The method of claim 1, wherein improved sleep includes one or
more of the following: increasing total nighttime sleep; or
reducing nighttime awakenings; or advancing sleep onset; or
reducing wake time; or reducing daytime naps.
3. The method of claim 2, wherein reducing nighttime awakenings
includes reducing a number of nighttime awakenings, reducing a
length of nighttime awakenings, or both.
4. The method of claim 2, wherein administering includes
administering the tasimelteon once daily between one-half hour and
two hours before bedtime.
5. The method of claim 4, wherein administering includes
administering the tasimelteon between one-half hour and
one-and-one-half hours before bedtime.
6. The method of claim 5, wherein administering includes
administering the tasimelteon one hour before bedtime.
7. The method of claim 1, wherein the amount of tasimelteon
effective to improve sleep in the patient is between about 5 mg/day
and about 100 mg/day.
8. The method of claim 7, wherein the amount of tasimelteon
effective to improve sleep in the patient is about 20 mg/day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of co-pending
U.S. patent application Ser. No. 16/848,150, filed 14 Apr. 2020,
which is a continuation of U.S. patent application Ser. No.
16/211,687, filed 6 Dec. 2018, now U.S. Pat. No. 10,653,665, which
is a continuation of U.S. patent application Ser. No. 15/326,934,
filed 17 Jan. 2017, now U.S. Pat. No. 10,179,119, issued 15 Jan.
2019, which is the US National Phase of PCT Patent Application
Serial No. PCT/US15/47610, filed 29 Aug. 2015, which claims the
benefit of US Provisional Patent Application Ser. No. 62/044,856,
filed 2 Sep. 2014, and 62/169,635, filed 2 Jun. 2015, each of which
is hereby incorporated herein as though fully set forth.
BACKGROUND
[0002] Smith-Magenis Syndrome (SMS) is a rare (1 in 25,000 births)
clinically-recognizable syndrome resulting from an interstitial
deletion of 17p11.2 or a mutation of the RAI1 gene.
[0003] SMS is characterized by a distinct pattern of minor
craniofacial and skeletal anomalies, expressive speech/language
delays, psychomotor and growth retardation, and a striking
neurobehavioral phenotype. This phenotype includes stereotypies,
self-injurious and aggressive behaviors.
[0004] A common symptom of SMS is a chronically disrupted sleep
pattern, which is found at all ages. Severe sleep disturbances are
virtually universal in SMS patients (75%-100%
individuals/caregivers report symptoms), thus representing a major
challenge to the patient and family. Sleep disturbances continue
across the lifespan; infants typically present with
hypersomnolence. Early in life, however, extreme sleep
disturbances, including difficulty falling asleep, inability to
enter or maintain REM (rapid eye movement) sleep, reduced night
sleep, shortened and broken sleep cycles with frequent night-time
and early morning awakenings and excessive daytime sleepiness,
begin in early toddlerhood and last into adulthood. Furthermore,
disturbed sleep appears to be the strongest predictor of
maladaptive behavior in children with SMS, including temper
tantrums, hyperactivity, attention deficits, and "sleep
attacks."
[0005] One of the likely contributing factors to these sleep
disturbances is an apparent "inverse" circadian pattern of the
hormone melatonin which is normally released only at night whereas
its production is inhibited by light. Several studies have reported
that plasma melatonin in SMS patients is high during the day and
low at night, which is opposite of the normal pattern. Whether this
apparent "inverted" melatonin secretion pattern is constant within
the same individual and universal across SMS patients is still
uncertain, as the underlying cause for this disrupted daytime
melatonin secretory pattern is unknown. However, findings reported
of two patients, whose melatonin secretory pattern and light
induced inhibition were normal, are significant because they
suggest that the sleep disturbances in SMS may not be solely
attributed to the abnormal diurnal melatonin secretion.
[0006] Significant progress has been made in the understanding of
the genetic basis of the SMS syndrome. However, the molecular basis
of the circadian rhythm disruption and of other specific features
of the phenotype have not been fully characterized and a greater
understanding of the cellular and molecular control of both the
circadian clock and pineal functioning will provide options for
pharmacological interventions that could address the most severe
symptoms of the disease. Until a precise understanding of the
biological anomaly present in SMS is obtained, treatment with
conventional drugs, like beta-blockers and exogenous melatonin (in
the US), will not satisfactorily improve aberrant sleep patterns
and behavior in SMS patients and therefore will not consistently
ease the burden on patients and their families. At the present
time, there is no effective treatment for sleep disturbances in
SMS.
SUMMARY OF THE INVENTION
[0007] In one embodiment, the invention provides a method for the
treatment of sleep disturbances in a patient with SMS that
comprises internally administering to the patient an effective
amount of tasimelteon daily.
[0008] In another embodiment, the invention provides a method of
treating a sleep disorder in an individual suffering from SMS, the
method comprising: inhibiting melatonin production in the
individual during waking hours; and administering to the individual
an effective amount of a melatonin agonist prior to sleep.
[0009] In another embodiment, the invention provides a method of
regulating melatonin production in an individual exhibiting
light-induced melatonin production, the method comprising:
inhibiting melatonin production in the individual during waking
hours; and stimulating melatonin production in the individual
during sleep.
[0010] In still another embodiment, the invention provides a method
of treating a sleep disorder in an individual suffering from SMS,
the method comprising: inhibiting melatonin production in the
individual during waking hours; and stimulating melatonin
production in the individual during sleep.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] These and other features of this invention will be more
readily understood from the following detailed description of the
various aspects of the invention taken in conjunction with the
accompanying drawings that depict various embodiments of the
invention, in which:
[0012] FIGS. 1-3 show measured cortisol levels and light exposure
levels for an individual with SMS during three consecutive days of
a study; and
[0013] FIGS. 4-6 show measured melatonin levels and light exposure
levels for an individual with SMS during three consecutive days of
a study.
[0014] It is noted that the drawings of the invention are not to
scale. The drawings are intended to depict only typical aspects of
the invention, and therefore should not be considered as limiting
the scope of the invention.
DETAILED DESCRIPTION
[0015] Applicants have carried out a study with the objectives to
characterize the circadian rhythms of individuals with SMS as
measured by plasma melatonin and cortisol, evaluate if there is an
association between the melatonin or cortisol circadian patterns
(delayed, advanced, Non-24, variable) and various aspects of the
SMS phenotype (ex: sleeping patterns, behavioral problems),
determine if there is an association between the characteristics of
the genetic mutation (e.g., extent of the 17p11.2 deletion, RAI1
mutation) and the levels and circadian patterns of melatonin and
cortisol and/or the response to a melatonin suppression test (MST),
and assess light sensitivity in individuals with SMS as determined
by a Melatonin Suppression Test (MST).
[0016] This study consisted of three phases: a screening phase
followed by an evaluation phase with an optional variable phase for
subjects whose circadian melatonin profile warrants further
investigation.
[0017] During the screening phase, participants were provided
consent/assent and initial eligibility was evaluated. Subjects were
asked to provide information regarding their prior SMS diagnosis,
to complete all baseline behavioral assessments and quality of life
questionnaires, and allow a blood sample to be obtained for genetic
testing. Samples were sent to a core genetic laboratory for a
detailed analysis of the RAI1 gene. Results of the analysis did not
need to be returned before subject began the trial if the diagnosis
meet eligibility criteria.
[0018] During the evaluation phase, three testing segments (TS1,
TS2, and TS3) were conducted one week apart at weeks 1, 2, and 4,
respectively. These segments included 36-hour melatonin and
cortisol assessments where blood samples were taken every hour from
an indwelling catheter. When the subject arrived for TS1, they were
fitted with an actigraphy watch to assess light exposure and
monitor activity. Blood samples were begun on the first night at
20:00 hours and continued hourly for 36 hours during each testing
period.
[0019] The variable phase consisted of an optional melatonin
suppression test (MST) for individuals determined to have a
delayed, advanced, or Non-24 circadian profile. During the MST,
plasma samples were collected every hour for the measurement of
melatonin. One to two hours after melatonin onset, subjects were
exposed to bright light for 180 minutes, with the exposure timed to
coincide with the expected peak in plasma melatonin concentrations.
During the period of light exposure, blood samples were collected
every 30 minutes.
Results
[0020] Eight participants, aged 7 to 35, with history of severe
sleep disturbances and a cytogenetic confirmed SMS diagnosis
completed the evaluation phase. The timing of the melatonin and
cortisol acrophases was consistent during the 4 week assessment,
with a circadian period of .about.24.0 hours. Melatonin secretion
occurred mainly during the daytime hours with a mean acrophase
between approximately 2:00 .mu.m and 5:30 pm and very low levels or
no melatonin produced during the nighttime, except for one
participant for whom the melatonin secretion acrophase occurred
around 5:00 am. The mean cortisol acrophase ranged from about 9:00
am to 11:30 am in all participants. The sleep/wake pattern recorded
by actigraphy showed a severely fragmented nighttime sleep period
with multiple bouts of activity, and daytime naps or periods of no
or little activity. These patterns were variable between
participants and between days.
[0021] Individuals with SMS showed an abnormal daytime, but stable,
secretion pattern of plasma melatonin believed to be responsible
for the severe sleep disorder. In contrast, their cortisol rhythm
appears to be normal. Individuals with SMS suffer from severe
nighttime sleep disturbances characterized in particular by
multiple periods of nighttime activity that frequently interrupt
the sleep period, resulting in poor sleep efficiency, variable
sleep onset and morning awakenings, and unpredictable sleep
quality.
[0022] The sleep disorder, which is believed to be the strongest
predictor of maladaptive behavior in SMS individuals, including
aggressive behavior, temper tantrums, hyperactivity, attention
deficits, constitutes a major challenge to the patients and their
families. Its detailed characterization is essential in developing
an effective treatment, which is crucially needed.
Tasimelteon
[0023] Tasimelteon is a circadian regulator which binds
specifically to two high affinity melatonin receptors, Mel1a (MT1R)
and Mel1b (MT2R). These receptors are found in high density in the
suprachiasmatic nucleus of the brain (SCN), which is responsible
for synchronizing our sleep/wake cycle. Tasimelteon has been shown
to improve sleep parameters in prior clinical studies, which
simulated a desynchronization of the circadian clock. Tasimelteon
has so far been studied in hundreds of individuals and has shown a
good tolerability profile.
[0024] Tasimelteon has the chemical name:
trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide,
has the structure of Formula I.
##STR00001##
[0025] Tasimelteon is disclosed in U.S. Pat. No. 5,856,529 and in
US Patent Application Publication No. 2009/0105333, both of which
are incorporated herein by reference as though fully set forth.
[0026] Tasimelteon is a white to off-white powder with a melting
point of about 78.degree. C. (DSC) and is very soluble or freely
soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate,
isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only
slightly soluble in water. The native pH of a saturated solution of
tasimelteon in water is 8.5 and its aqueous solubility is
practically unaffected by pH. Tasimelteon has 2-4 times greater
affinity for MT2R relative to MT1R. Its affinity (K.sub.i) for MT1R
is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in
the practice of this invention because it is a melatonin
agonist.
[0027] In related aspects, this invention relates to the use of a
tasimelteon metabolite as the melatonin agonist. Tasimelteon
metabolites include, for example, a phenol-carboxylic acid analog
(M9) and a hydroxypropyl-phenol analog (M11). Each is formed in
humans following oral administration of tasimelteon.
[0028] Specifically, aspects of the invention encompass use of
tasimelteon or of compounds of Formulas II or III, including salts,
solvates, and hydrates of tasimelteon or of compounds of Formula II
or Formula III, in amorphous or crystalline form.
##STR00002##
[0029] While depicted herein in the R-trans configuration, the
invention nevertheless comprises use of stereoisomers thereof,
i.e., R-cis, S-trans, and S-cis. In addition, the invention
comprises use of prodrugs of tasimelteon or of compounds of Formula
II or of Formula III, including, for example, esters of such
compounds. The discussion that follows will refer to tasimelteon
but it is to be understood that the compounds of Formula II and III
are also useful in the practice of aspects of the invention.
[0030] Metabolites of tasimelteon include, for example, those
described in "Preclinical Pharmacokinetics and Metabolism of
BMS-214778, a Novel Melatonin Receptor Agonist" by Vachharajani et
al., J. Pharmaceutical Sci., 92(4):760-772, which is hereby
incorporated herein by reference. The active metabolites of
tasimelteon can also be used in the method of this invention, as
can pharmaceutically acceptable salts of tasimelteon or of its
active metabolites. For example, in addition to metabolites of
Formula II and III, above, metabolites of tasimelteon also include
the monohydroxylated analogs M13 of Formula W, M12 of Formula V,
and M14 of Formula VI.
##STR00003##
[0031] Tasimelteon can be synthesized by procedures known in the
art. The preparation of a 4-vinyl-2,3-dihydrobenzofuran cyclopropyl
intermediate can be carried out as described in U.S. Pat. No.
7,754,902, which is incorporated herein by reference as though
fully set forth.
[0032] Pro-drugs, e.g., esters, and pharmaceutically acceptable
salts can be prepared by exercise of routine skill in the art.
Treatment of SMS-Related Sleep Disturbances
[0033] In at least some individuals with SMS, melatonin production
increases with light exposure--light-induced melatonin
production--a pattern opposite that expected. For example, FIGS.
4-6 show melatonin secretion (thick line) and a patient's light
exposure (thin line) during days 1, 2, and 3 of the study. A strong
correlation is seen between light exposure and melatonin
production. FIGS. 1-3 show similar results for a patient's cortisol
secretion (thick line).
[0034] The disrupted sleep patterns of SMS patients--or other
individuals exhibiting light-induced melatonin production--may be
treated by inhibiting melatonin production during waking hours
and/or increasing melatonin production during sleep. For example,
melatonin production may be inhibited by reducing exposure of the
individual's eyes to light using, for example, light blocking or
light filtering eyewear. Such eyewear may include eyeglasses,
contact lenses, etc., as will be apparent to one skilled in the
art. Light filtering eyewear may be operable to filter a broad
spectrum of light or, for example, a wavelength or range of
wavelengths determined to stimulate melatonin production.
[0035] In other embodiments of the invention, melatonin production
may be inhibited by administering to the individual an effective
amount of a beta blocker. In some embodiments of the invention,
such administration may be made using a device operable to deliver
to the individual a dosage of a beta blocker in proportion to the
individual's exposure to light as measured, for example, using a
light sensor, light meter, or similar apparatus in communication
with or incorporated into the device.
[0036] Increasing melatonin production may include administering a
melatonin agonist to the individual. In some embodiments of the
invention, the melatonin agonist may be tasimelteon and may be
administered at a dosage of between about 5 mg and 100 mg, e.g.,
between about 20 mg and about 50 mg, e.g., about 20 mg once daily
prior to sleep, e.g., between about 0.5 hours and about 1.5 hours
prior to sleep, e.g., about 1 hour prior to sleep.
[0037] Improvements in sleep disturbances may be measured in any
number of ways, including, for example, improvement in nighttime
sleep, which may include a reduction in the percentage of wake
period within the patient's sleep interval; improvement in one or
more of the following: total amount of nighttime sleep; number,
timing, and length of nighttime awakenings; sleep onset; wake time;
number, timing, and length of daytime naps; improvement in clinical
global impression of change (CGI-C); improvement in clinical global
impression of severity (CGI-S); and improvement in behavior.
[0038] In the case of treatment with tasimelteon administration,
treatment effects may be maintained by ongoing daily administration
of tasimelteon. Tasimelteon administration may, according to some
embodiments of the invention, be combined with the inhibition of
melatonin activity in the patient during waking hours by, for
example, one or more of: reducing the exposure of the patient's
eyes to light, internally administering to the patient an active
pharmaceutical ingredient that inhibits melatonin production, or
internally administering to the patient an active pharmaceutical
ingredient that antagonizes melatonin activity
[0039] Other aspects and embodiments of the invention will be
apparent to one skilled in the art from the description above and
the appended summary of the study and are within the scope of the
invention.
* * * * *