CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

205677Orig1s000
RISK ASSESSMENT and RISK MITIGATION
REVIEW(S)

 Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Surveillance and Epidemiology
Office of Medication Error Prevention and Risk Management
Risk Evaluation and Mitigation Strategy (REMS) Memo

Date:

October 22, 2013

Reviewer(s):

Nyedra W. Booker, Pharm.D., M.P.H., Risk Management
Analyst, Division of Risk Management (DRISK)

Team Leader:

Kendra Worthy, Pharm.D., DRISK

Division Director:

Claudia Manzo, Pharm.D., DRISK

Drug Name(s):

tasimelteon

Therapeutic Class:

Circadian Regulator (first in class)

Dosage and Route:

20 mg oral capsules

Indication(s):

Treatment of Non-24-hour disorder in blind individuals
with no light perception

Application Type/Number:

NDA 205-677

Applicant/sponsor:

Vanda Pharmaceuticals, Inc.

OSE RCM #:

2013-1559

*** This document contains proprietary and confidential information that should not be
released to the public. ***

Reference ID: 3394589

 1

INTRODUCTION

This review documents the Division of Risk Management (DRISK) evaluation of the
NDA 205-677 for tasimelteon, an NME, to assess the need for a Risk Evaluation and
Mitigation Strategy.
Tasimelteon is the first circadian regulator in clinical development for the treatment of
Non-24-hour disorder in blind patients with no light perception (total blindness). Non-24hour disorder (Non-24) is also referred to as:


Circadian rhythm sleep disorder-non-entrained type



Non-24-hour circadian rhythm disorder



Circadian rhythm sleep disorder- free-running type



Free running disorder (FRD)



Non-24-hour sleep-wake disorder



Hypernychthemeral disorder

The recommended dose of tasimelteon is 20 mg per day taken
prior to bedtime,
preferably at the same time every night. The draft label states that tasimelteon can be
(b) (4)
taken
without food.
(b) (4)

2

3

MATERIALS REVIEWED


Clinical Overview, Vanda Pharmaceuticals Inc., dated May 31, 2013



NDA 225-677 Tasimelteon Mid-Cycle Meeting Clinical Review-slides (D.
Jillapalli), dated September 12, 2013



NDA 225-677 Tasimelteon Mid-Cycle Meeting Clinical Pharmacology Reviewslides (J. Parepally), dated September 12, 2013

OVERVIEW OF CLINICAL PROGRAM

Tasimelteon is a circadian regulator that resets the body’s master clock in the
suprachiasmatic nucleus (SCN) of the hypothalamus by binding to melatonin MT1 and
MT2 receptors, with an approximate 2-4x greater affinity for MT2. The clinical program
for tasimelteon included over 1,300 patients and healthy volunteers. The trials were
designed to demonstrate the drug’s safety and effectiveness as a circadian regulator to
treat Non-24-hour disorder1 in patients with total blindness, and as a circadian regulator
in healthy individuals2.

1

Study criterion for diagnosis of Non-24 was determined based on the following: 1) history (within the past
3 months) of difficulty sleeping at night (difficulty with sleep initiation or maintenance), difficulty
awakening in the morning, or daytime sleepiness and, 2) demonstration of progressive delay of aMT6s
acrophase time.

2

Vanda Pharmaceuticals, Inc. Pharmacovigilance Plan (NDA 205677).

1
Reference ID: 3394589

 Safety and Efficacy Trials
Efficacy
Tasimelteon’s effectiveness as a circadian regulator in the treatment of Non-24 in totally
blind individuals was established through two randomized, double-blind, placebocontrolled, parallel-group trials plus a parallel-group trial in healthy volunteers:


26-week randomized, open-label study (with an open-label extension)
Non-24 patients (N=84) with non-entrained melatonin circadian rhythms
(circadian period (Ʈ) length ≥24.25hrs) at baseline and a sleep-wake complaint
were randomized to receive 20 mg tasimelteon or placebo one hour before
bedtime at the same time daily for a 6-month treatment period. Entrainment of
urinary aMT6s (a major metabolite of melatonin) and cortisol was measured at
screening, then during weeks 2 through 5 of the study.



20-24 week randomized withdrawal trial
Non-24 patients from the open-label study who responded to tasimelteon
treatment as measured by aMT6s and Ʈ≤24.1 hours (N=20), were included in this
study. The study was designed to evaluate tasimelteon’s maintenance effect after
long-term use. Patients were randomized to receive 20 mg tasimelteon or placebo
daily (one hour before bedtime) for approximately 12 weeks. Those achieving
melatonin circadian rhythm entrainment during the run-in phase were
subsequently randomized to receive continued treatment with 20 mg tasimelteon
or placebo for an additional 8 weeks.



3-day study involving healthy volunteers (N=39) using tasimelteon (10, 20, 50
and 100 mg) or placebo oral capsules once daily. This study was conducted to
assess tasimelteon’s efficacy as a circadian regulator.

Primary efficacy endpoints: 1) entrainment of circadian rhythms (measured by aMT6s)
and 2) clinical response (measured by demonstration of entrainment of aMT6s and a
Non-24 Clinical Response Scale (N24CRS)3 score≥3) were both achieved in the
randomized, controlled trial. Significantly more tasimelteon-treated patients achieved
more frequent entrainment compared to placebo (p=0.0171), and more tasimelteontreated patients achieved entrainment associated with significant clinical improvement, as
measured by N24CRS scores (p=0.0028). The secondary endpoint “entrainment of the
cortisol rhythm” was also achieved (p=0.0313).
Statistical significance was achieved in the randomized withdrawal trial for the primary
endpoint “maintenance of effect of tasimelteon to entrain circadian rhythms” in Non-24
patients, as measured by urinary aMT6s (p=0.0026), and the secondary endpoint
“maintenance of entrainment of the cortisol rhythm” (p=0.0118).

3

Non-24 Clinical Response Scale (N24CRS) is a composite scale of endpoints for measuring clinical
improvement in nighttime sleep, daytime sleep duration, sleep timing and global functioning.

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Reference ID: 3394589

 Safety
Tasimelteon’s safety was established based on a pooled analysis of available safety data
across all clinical trials [a total of 23 clinical studies: safety, efficacy, pharmacokinetic
(PK), pharmacodynamic (PD) and “thorough QT” to assess effects on QT interval].
Long-term safety was established in a 6 month open-label extension of the 26-week
randomized/26-week open-label trial, and in the following two open label studies:
 52 weeks followed by a 3 year optional sub-study involving (N=140; “planned”)
totally blind subjects with Non-24 disorder using tasimelteon 20 mg oral capsules
once daily.
 2-year study involving (N=200; “planned”) totally blind subjects with Non-24
disorder using tasimelteon 20 mg oral capsules once daily.
The most frequently reported adverse events (AEs) in all subjects (tasimelteon and
placebo-treated) included headache, “vivid or unusual dreams”, somnolence,
nasopharyngitis, urinary tract infections and increases in alanine aminotransferase (ALT).
Events were typically reported within the first 30 days post-treatment initiation.
Headache and “vivid or unusual dreams” were the two AEs reported with higher
frequency in tasimelteon-treated subjects to an extent that was “clinically meaningful”
according to the sponsor.
The discontinuation rate (overall and adverse-events specific) between the tasimelteon
and placebo groups was comparable [tasimelteon (7.1% and 2.5%); placebo (6.9% and
2.3%)]. Significantly more tasimelteon-treated subjects, however, experienced AEs in the
“Nervous Systems Disorders” and “Psychiatric Disorders” system-organ classes (SOCs)
as compared to the placebo group.
Agency Findings
In March 2007, the Agency requested that all manufacturers of sleep disorder (sedativehypnotic) drug products strengthen their product labeling (including the development of
patient Medication Guides) to include stronger language concerning potential risks
including severe allergic reactions and complex sleep-related behaviors such as sleepdriving.4
A Medication Guide was not included in the sponsor’s original submission. The Agency
notified the sponsor on June 20, 2013 that a Medication Guide (using approved sedativehypnotics as a model) would be required, and the sponsor subsequently proposed a
(b) (4)
Medication Guide to be available in
Clinical reviewer Dr. Devanand Jillapalli discussed the clinical program for tasimelteon
during the Mid-cycle meeting and concluded that no major safety issues had been
identified thus far. Clinical pharmacology reviewer Dr. Jagan Parepally presented study
findings related to the effect of intrinsic factors (e.g., age, gender, renal and hepatic
function) on tasimelteon’s exposure. According to Dr. Parepally, tasimelteon plasma
4

FDA NEWS RELEASE. FDA Requests Label Change for All Sleep Disorder Drug Products. March 14,
2007.

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 concentration (as measured by Cmax and AUC) increased 2 fold in the elderly compared
to adults, and the AUC by 43% and 90% in patients with mild and moderate hepatic
impairment respectively. The preliminary recommendation was to reduce the tasimelteon
dose to 10 mg for the elderly and patients with moderate hepatic impairment.
At the time of this review, a Peripheral and Central Nervous System Drugs (PCNS)
Advisory Committee meeting has been scheduled for November 14, 2013.
4

DISCUSSION

Non-24 hour disorder is a condition that affects approximately 100,000 individuals in the
U.S. Non-24 is characterized by a sleep-wake cycle that lacks synchronization to the 24hour environment, which can occur when “synchronizing input” such as the
environment’s light-dark cycle has been compromised. Blind patients who have
diminished or complete absence of light perception are at significantly increased risk for
Non-24, and more than 50% are believed to have the condition.56 Patients with Non-24
often experience significant impairment in social and occupational functioning.
There are no sleep disorder (sedative-hypnotic) drugs currently approved to treat Non-24
hour disorder. In addition, none of the approved sleep disorder drugs have REMS
program requirements.
Tasimelteon appears to demonstrate clinical benefit in Non-24 hour disorder patients with
total blindness, and the adverse event profile thus far is favorable according to the clinical
review team. There are no serious risks identified at this time to warrant a REMS.
Adverse events of concern will be addressed in the labeling.
5

CONCLUSION

DRISK believes that a REMS for tasimelteon is not necessary at this time to ensure the
benefits outweigh the risks. The inclusion of a Medication Guide and the sponsor’s
proposal for labeling and routine pharmacovigilance are reasonable. Should DNP identify
additional safety information that warrants risk mitigation measures, please send a
consult to DRISK.

5

Harrison’s Principles of Internal Medicine (18e)/Harrison’s Online. Chapter 27 (Sleep Disorders).

6

Zee PC, Attarian H, Videnovic A. Circadian Rhythm Abnormalities. American Academy of Neurology
(Continuum Review Article) 2013; 199(1):132-147.

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Reference ID: 3394589

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------NYEDRA W BOOKER
10/22/2013
CLAUDIA B MANZO
10/22/2013
concur

Reference ID: 3394589