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Pleiomorphic Expression of N24HSWD in the Totally Blind
Licamele L, Dressman M, Feeney J, Polymeropoulos MH
Vanda Pharmaceuticals Inc., Washington, DC
A b s t r a c t (0611)
Introduction: Non-24-hour sleep-wake disorder (N24HSWD) is a
circadian rhythm sleep disorder that occurs when individuals are
unable to synchronize their endogenous circadian rhythm to the
24-hour day. N24HSWD is most commonly found in blind subjects
lacking the ability to perceive light, the primary zeitgeiber for
synchronizing the circadian system daily. In general, individuals
with N24HSWD suffer from a variety of clinical symptoms as they
cycle in-to and out-of phase. We investigated the variability of
sleep related clinical symptoms across individuals characterized as
having N24HSWD.
Discussion
Results
Subtype I (8%)
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Subtype II (61%)
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Methods: The SET study is an ongoing multicenter, doublemasked, placebo-controlled, parallel study to investigate the Safety
and Efficacy of Tasimelteon in subjects with N24HSWD. During the
screening phase subjects maintained daily sleep diaries. The
length of a subject’s circadian cycle was determined by measuring
the melatonin metabolite, 6-sulphatoxymelatonin (aMT6s).
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Subtype IV (4%)
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 Only
30% of participants exhibited cyclic sleep-wake patterns
(Subtypes III and IV) despite all participants having a confirmed
non-24-hour melatonin rhythm
 A minority
(<10%) of individuals exhibited no evidence of sleep
disturbance (Subtype I) and the majority (60%) exhibited sleep
complaints but with no evidence of a cyclic disturbance (Subtype
II)
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Sleep-Wake Disorder (N24HSWD) is a chronic
circadian rhythm disorder that occurs when the endogenous
circadian pacemaker is not synchronized to the 24-hour light-dark
cycle resulting in symptoms of insomnia and/or excessive
sleepiness. The endogenous periodicity is typically greater than
24 hours leading to a daily delaying of phase1-4
 Tasimelteon
is being developed for the chronic treatment of
N24HSWD, a serious circadian sleep-wake disorder
 The SET study is
the largest placebo controlled efficacy study to
be conducted in this population (ClinicalTrials.gov NCT01163032)
 Tasimelteon, a circadian regulator, is a dual melatonin MT1/MT2
receptor agonist
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shifting endogenous circadian
rhythms5
 In sighted people, light, as perceived by the eyes and transmitted
to the suprachiasmatic nucleus (SCN), is the master circadian
regulator which entrains the endogenous clock to a 24-hour cycle
to coincide with the social/environmental 24-hour clock
 In
the absence of the ability to perceive light, the endogenous
clock cannot be entrained and the circadian rhythms cycle with a
frequency equal to that of the endogenous clock
 The result of this circadian period, which is different than the 24-
hour day, is the gradual shifting of the endogenous rhythm as
compared to the social/environmental 24-hour clock
 Timing
of melatonin secretion is the most well established and
accepted measurement of the circadian clock in humans6,7
 The
endogenous circadian period (τ) is a useful diagnostic for
N24HSWD
 The
traditional clinical definition of this disorder describes “a
pattern of sleep and wake times that typically delays each day
with a period longer than 24 hours” (ICSD-2)8
 Previous
studies, however, have shown that most patients with
non-entrained circadian rhythms do not experience these
symptoms and have highly variable sleep phenotypes, with widely
varying degrees of cyclic nighttime sleep and daytime napping
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aim of this poster is to assess the variability in sleep
phenotypes in over 100 totally blind patients with non-entrained
melatonin rhythms
Conclusion
 Totally
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blind individuals have a high prevalence of non-24-hour
circadian rhythms, as measured using strongly endogenous
circadian markers such as melatonin
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 Sleep patterns in totally blind individuals with confirmed non-24-
hour circadian rhythms are highly variable and do not have a
standard phenotype
 Observation
Subtype I: Patient reports a sleep complaint but the
daily sleep diaries reveal no evidence of a major sleep
disturbance or cyclic sleep-wake pattern; absent or
minimal daytime naps; indistinguishable from normal
sleep
Subtype II: Evidence of sleep disturbance without
evidence of a cyclic sleep-wake pattern; daytime naps
present but without a recognizable pattern
Methods
Study Design
 Data were collected as part of the SET study, an ongoing multicenter, double-masked,
placebo-controlled, parallel study to investigate the Safety and Efficacy of Tasimelteon
in subjects with N24HSWD (ClinicalTrials.gov NCT01163032)
 Totally blind subjects were primarily recruited from a registry (Poster 45) and screened
at 26 clinical sites across in the United States and Germany
 Tasimelteon has been shown in clinical studies to be capable of
external factors; for example, patients in Subtype III may have
cyclic patterns of sleep latency, nighttime sleep duration or
daytime naps either alone or in combination
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Introduction
 Non-24-Hour
 There can be variability in the expression of each subtype due to
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Conclusion: These finding suggest that while circadian
desynchrony typically results in cyclical episodes of poor nighttime
sleep and increased daytime sleepiness, the expression can be
variable across individuals. Some patients have a cyclical
nighttime sleep deficit accompanied by cyclical occurrence of
daytime naps. Others have only the cyclical nighttime sleep deficit
but no cyclical naps. For some patients, the sleep deficit and the
daytime naps may be non-cyclical. N24HSWD is a pervasive
disorder with significant inter-patient variability in sleep and nap
expression, requiring detailed evaluation to identify the disorder.
than 5% of individuals matched the traditional textbook
definition of N24HSWD (Subtype IV) with a clearly non-24-hour
sleep period
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 Less
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categorized into four pre-defined sleep subtypes
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Results: As a population, N24HSWD individuals suffer from a
significant deficit of nighttime sleep as well as an increase in
daytime somnolence when they are out-of-phase. Examination of
the data on an individual level demonstrates that the expression of
these clinical symptoms varies greatly. We present data from
several individuals that exhibit a non-24 hour circadian cycle, but
who suffer from variable sleep related clinical symptoms.
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Subtype III (26%)
 Participants with confirmed non-24-hour circadian rhythms
Subtype III: Evidence of a cyclic sleep-wake pattern
while maintaining the major sleep episode at night
(relative co-ordination); daytime naps may be present
with a cyclic recurrence coincident with nighttime sleep
disturbance; patient may report cyclic sleep problems
excretion rate (ng/h) was plotted against the midpoint of each collection
episode and fitted with a cosine function to determine peak (acrophase) time (red
stars)
 Circadian
period (τ) was calculated using weighted linear analysis of the serial
acrophase times over 4 weeks
 Only those with τ > 24.1 without 95% CI crossing 0 (24 h) were included
Raster Plots
 Sleep-wake onset and offset times, and daytime naps, were double plotted in raster
format and overlaid with aMT6s acrophase time
of the sleep problem, patients with non-24-hour
circadian rhythms may be at risk for other circadian-related
disorders, for example metabolic disorders as a result of eating at
the incorrect circadian phase
 Diagnostic standards need to be revised to include measures of
strongly endogenous circadian
melatonin and cortisol rhythms
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0
markers
such
as
24-hour
Acknowledgements
I
II
III
IV
 We would like to thank all of the individuals that
participated in
this clinical study to help further the understanding of N24HSWD.
Without their participation this work would not be possible
 We would
also like to acknowledge Dr. Steven W. Lockley for his
expertise and help in reviewing this poster
 Participants completed a daily sleep and nap diary during the screening phase of the
 aMT6s
 Regardless
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 18-75 years of age with no perception of light by self-report
Circadian Period (τ) and Phase Calculation
 Circadian phase was determined from urinary 6-sulphatoxymelatonin (aMT6s)
collected for 48 hours per week for at least 4 weeks. aMT6s was measured by a Liquid
Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS)
disorder awareness and diagnosis rates are low
and should be improved to ensure appropriate care for this
population
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SET study by calling an interactive voice recognition system twice daily. Subjects were
asked to maintain a fixed 9-hour sleep episode of their choice starting between 2100100 h (dashed gray lines)
 Consequently,
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awakening in the morning, or daytime sleepiness within the last 3 months as
determined by the Sleep Complaint Questionnaire
Subtype IV: Evidence of a clear Non-24 pattern in the
major sleep episode; naps may not be present if there
is a consolidated main sleep episode; patient reports
cyclic sleep problems in relation to 24-h day
Figure 1: Prevalence of Four Subtypes of Non-24
Inclusion Criteria
 Data were collected as part of an ongoing multicenter, double-masked, placebocontrolled study to investigate the Safety and Efficacy of Tasimelteon in subjects with
N24HSWD
 History of trouble sleeping at night (difficulty initiating sleep or staying asleep), difficulty
of sleep-wake cycles without additional measures
cannot accurately detect non-24-hour circadian rhythms, even
with 100+ days of sleep data. The ICSD diagnostic criteria require
only 7 days of sleep-wake data, further confounding the
appropriate diagnosis in a patient suffering with non-24-hour
circadian rhythms
Figure 2: Circadian Phase Assessment
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Lockley et al. J. Clin. Endocrinol . Metab. 1997, 82: 3763-3770.
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 Individuals were classified into one of four sleep phenotype subtypes (see Results)
The information presented here concerns a use that has not been approved by the U.S. Food and Drug Administration
Presented at the 26th Annual Meeting of the Associated Professional Sleep Societies, LLC
June 10, 2012; Boston, MA