Efficacy and Safety of Tasimelteon Compared With Placebo in Totally Blind Subjects With Non-24-Hour Sleep-Wake Disorder

Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals, primarily those without
light perception, are unable to synchronize their endogenous circadian pacemaker to the
24-hour light-dark cycle, and the timing of their circadian rhythm instead reflects the
intrinsic period of their endogenous circadian pacemaker. As a result, the circadian rhythm
of sleep-wake propensity in these individuals moves gradually later and later each day if
there circadian period is > 24 hours and earlier and earlier if < 24 hours. These
individuals will be able to sleep well at night when their sleep-wake propensity rhythm is
approximately aligned with the 24-hour light-dark and social cycle. However, after a short
time, the endogenous sleep-wake propensity rhythm and the 24-hour light-dark cycle will move
out of synchrony with each other, and they may have difficulty falling asleep until well
into the night. In addition to problems sleeping at the desired time, the subjects
experience daytime sleepiness and daytime napping.

This will be a multicenter, randomized, double-masked, placebo-controlled, parallel study.
The study has two phases: the pre-randomization phase followed by either the randomization
phase or the open-label extension (OLE). The pre-randomization phase comprises a screening
visit where subject's initial eligibility will be evaluated, a circadian period (τ)
estimation segment, and a variable-length in-phase transition segment in which subjects will
wait to start treatment until their circadian phase is aligned with their target bedtime.
Subjects that meet all entry criteria for the study will enter the randomization phase.
During the randomization phase, subjects will be asked to take either 20 mg tasimelteon or
placebo approximately 1 hour prior to their target bedtime for 26 weeks in a double-masked
fashion. Subjects who have a tau greater than 24.0 and meet all entry criteria but that are
ineligible for the randomization phase due to their τ estimate may be given the opportunity
to participate in the OLE phase. During the OLE phase, subjects will take open-label 20mg
tasimelteon for 26 weeks.

Inclusion Criteria:

- Ability and acceptance to provide informed consent;

- No perception of light by the subject's own report;

- Diagnosis of N24HSWD as determined by:

1. History (within the last 3 months) of trouble sleeping at night difficulty
initiating sleep or staying asleep), difficulty awakening in the morning, or
daytime sleepiness as determined by answering yes to at least one question in
the Sleep Complaint Questionnaire and

2. Urinary aMT6s demonstrates a progressive delay of the aMT6 acrophase time.

- Willing and able to comply with study requirements and restrictions including a
commitment to a fixed 9-hour sleep opportunity during the study;

- Fluent in English;

Exclusion Criteria:

- Have a probable diagnosis of a current sleep disorder other than N24HSWD that is the
primary cause of the sleep disturbance based on clinical investigator medical
judgment;

- Current clinically significant cardiovascular, respiratory, neurologic, hepatic,
hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently
controlled and stable;

- History (within the 12 months prior to screening) of psychiatric disorders including
Major Depressive Disorder, Generalized Anxiety Disorder, Axis II Disorders, delirium
or any other psychiatric disorder that in the opinion of the clinical investigator
would affect participation in the study or full compliance with study procedures;

- History of intolerance and/or hypersensitivity to melatonin or melatonin agonists;

- Worked night, rotating, or split (period of work, followed by break, and then return
to work) shift work within 1 month of the screening visit or plan to work these
shifts during the study;

- Unable to perform calls to the study IVR system to report questionnaire results;

- Exposure to any investigational drug, including placebo, within 30 days or 5 half
lives (whichever was longer) of screening;

- Use of central nervous system prescription or OTC medications, other than melatonin,
that affects the sleep-wake cycle

- Use of melatonin or melatonin agonist