Tasimelteon for the Treatment of Non-24-hour Sleep-Wake Disorder (N24HSWD) in Blind Individuals With no Light Perception

Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals 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 is < 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. As time
progresses, the endogenous circadian rhythm of sleep-wake propensity in these individuals
moves further and further away from the 24-hour light-dark cycle and gradually, these
individuals are unable to sleep at night and as a result experience extreme sleepiness
during the daytime hours and more frequent naps with a longer duration. Eventually, the
sleep-wake time moves back into alignment with the social time for sleep and the individuals
sleep well at night and have decreased daytime napping. The alignment between their
endogenous circadian rhythms and the 24-hour day is temporary as they are continually
drifting later and later each day.

The study is comprised of one 24-month treatment phase, as all subjects enrolled in the
trial have already been diagnosed with N24HSWD. Frequency of study visits will depend on the
subject's prior length of exposure to tasimelteon; accordingly, subjects will be assigned to
one of two groups upon enrollment into the study. The short-term exposure group will consist
of subjects for which it is possible at screening that they have been exposed to tasimelteon
for less than 6 months. The long-term exposure group will consist of subjects who have more
than 6 months of exposure to tasimelteon.

After completion of the 24-month treatment phase, subjects have the option to enroll into
the optional open-label extension sub-study for an additional 52 weeks. Frequency of visits
will be identical regardless of previous exposure (short term/long term).

Inclusion Criteria:

1. Ability and acceptance to provide informed consent;

2. Men or women at least 18 years of age or older who meet one of the following:

- Has enrolled in VP-VEC-162-3201 (with sponsor approval)

- Has completed VP-VEC-162-3203

- Was deemed a non-responder in VP-VEC-162-3203

- Has enrolled in VP-VEC-162-3203 (with sponsor approval)

- Has a previous diagnosis of N24HSWD

- The subject is totally blind and meets the following Diagnostic and Statistical
Manual of Mental Disorders 5 diagnostic criteria

- A persistent or recurrent pattern of sleep disruption that is primarily due
to an alteration of the circadian system or to a misalignment between the
endogenous circadian rhythm and the sleep-wake schedule required by an
individual's physical environment or social or professional schedule.

- The sleep disruption leads to excessive sleepiness or insomnia, or both.

- The sleep disturbance causes clinically significant distress or impairment
in social, occupational, and other important areas of functioning.

Specifically: A pattern of sleep-wake cycles that is not synchronized to the 24-hour
environment, with a consistent daily drift (usually to later and later times) of
sleep onset and wake times.

3. For US participants only: Males, non-fecund females (i.e., surgically sterilized,if
procedure was done 6 months before screening or subject is postmenopausal, without
menses for 6 months before screening), or females of child-bearing potential using an
acceptable method of birth control for a period of 35 days before the first dosing
during the study and for one month following the last dose and must have a negative
pregnancy test at the screening and baseline visits Note: Women using hormonal
methods of birth control must use an additional method of birth control during the
study and for one month after the last dose.

4. Diagnosis of N24HSWD in a previous tasimelteon study;

5. Willing and able to comply with study requirements and restrictions;

Exclusion Criteria:

1. 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;

2. History of intolerance and/or hypersensitivity to melatonin or melatonin agonists;

3. History of drug or alcohol abuse as defined in DSM-IV, Diagnostic Criteria for Drug
and Alcohol Abuse, within the 12 months prior to screening and/or regular consumption
of alcoholic drinks (> 40g/day);

4. Patients having any current suicidal ideation of type 4 or 5 on the C-SSRS at
Screening or Baseline;

5. Patient is at risk of suicide, in the opinion of the Investigator. Evidence of
suicide risk could include any suicide attempt within the past year or any other
suicidal behavior within the past year;

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

7. Clinically significant deviation from normal in vital signs measurements, or physical
examination findings at screening or baseline as determined by the clinical
investigator;

8. Pregnant or lactating females;

9. Smoke more than 10 cigarettes/day;

10. Exposure to any investigational drug other than tasimelteon, including placebo,
within 30 days, 5 half-lives, or the exclusion period given by a previous study in
which the patient has participated in, whichever of the three scenarios is longer.

11. Unwilling or unable to discontinue usage of medication listed in Section 8.2.1;

12. Any other sound medical reason as determined by the clinical investigator.