Tasimelteon

Unassigned

New Medicines

Hetlioz · Non-24-hour sleep wake disorder (N24HSWD) in totally blind adults

Information

Hetlioz
New molecular entity
Vanda Pharmaceuticals
Vanda Pharmaceuticals

Development and Regulatory status

Licensed but not launched
Launched
Launched
Yes
01. Aug 10: PIII study started [1]
02. Mar 11: Tasimelteon granted orphan drug status in the EU for Non-24-Hour Sleep/Wake Disorder (N24HSWD) in blind individuals with no light perception [2].
03. Dec 12: Vanda plans to file in the US in mid-2013 [5].
04. May 13: New Drug Application (NDA) submitted to FDA for tasimelteon, for the treatment of Non-24-Hour Disorder (Non-24) in the totally blind. Tasimelteon was developed to address a significant unmet medical need, the treatment of Non-24, for which there are currently no FDA approved products. [8]
05. Aug 13: Granted priority review in the US with a decision on approval expected by January 31, 2014 [10].
06. Nov 13: An FDA briefing for the CNS advisory panel meeting recommends approval of tasimelteon stating that evidence supports use in the treatment of circadian rhythm disorders in patients with Non-24 Hour Disorder who are totally blind, and there are no serious adverse events to consider. The recommendation is notable as Vanda and the FDA did not initially agree on a primary endpoint for the pivotal study but the FDA subsequently agreed to consider nighttime sleep and daytime naps as a likely indicator of efficacy [11].
07. Nov 13: The FDA Peripheral and Central Nervous System Drugs Advisory Committee voted overwhelmingly to recommend the approval of tasimelteon, for the treatment of Non-24-Hour Disorder (Non-24) in the totally blind [12].
08. Jan 14: Approved in US. to treat non-24- hour sleep-wake disorder (non-24) in totally blind individuals. Non-24 is a chronic circadian rhythm (body clock) disorder in the blind that causes problems with the timing of sleep. [13]
09. Feb 14: Hetlioz has orphan-product designation in the US. It will be launched in the US in 2Q 14 [14].
10. Apr 14: Launched in the US [15]
11. Jun 14: EU filing for the treatment of non-24-hour sleep-wake disorder in the blind accepted by the EMA [16].
12. Sep 14: Vanda initiates the HELITOZAccess Named Patient Programme in the EU and Canada, where tasimelteon regulatory approvals are being sought [17].
13. Apr 15: EU positive opinion for treatment of non-24-hour sleep-wake disorder (non-24) in totally blind adults [18].
14. Jul 15: EC approved HETLIOZ® (tasimelteon) for non-24-Hour sleep-wake disorder (Non-24) in totally blind adults. The marketing authorisation allows for the marketing of HETLIOZ® in all 28 EU member states as well as European Economic Area members Iceland, Liechtenstein and Norway. The EC has also confirmed orphan drug designation for HETLIOZ® for the treatment of Non-24 in totally blind adults [19].
15. Aug 16: Launched in Germany [22].
16. May 17: Launch in UK is planned but no date has yet been decided [23].
17. May 19: Vanda has yet to decide on UK launch plans [24].

Category

Melatonin agonist binding to two receptors, Mel1a (MT1R) and Mel1b (MT2R) [1].
N24HSWD is an orphan indication affecting ~140,000 in EU [1]. It occurs mainly in totally blind people who can't synchronise the brain's master body clock with the 24hr day-night cycle. Most people have a master body clock that naturally runs >24hrs; light is the main environmental cue resetting it to 24hrs each day. Those with non-24 have a master body clock that continually delays, putting them to later each day, turning night into day and day into night, until the cycle restarts again [7]
Non-24-hour sleep wake disorder (N24HSWD) in totally blind adults
Oral

Trial or other data

01. The goal of treatment is to synchronize circadian rhythms into an appropriate phase relationship with the 24-hour day with increased sleepiness during the night and increased wakefulness during the day [1].
02. Aug 10: a PIII trial (VP-VEC-162-3201) to evaluate tasimelteon 20mg vs placebo in 160 patients with Non-24-Hour Sleep Wake Disorder (N24HSWD), a condition experienced primarily by totally blind individuals that results in abnormal night sleep patterns and chronic daytime sleepiness has started. The study includes a 6-month treatment period and an optional open-label extension. The primary endpoint is improvement in Total Sleep Time (TST) during the night. The study will also measure parameters of daytime sleep and laboratory measures of the synchronization between the internal body clock and the 24-hour environmental light/dark cycle. Top-line results are expected 4Q 2011 [1].
03. Jan 12: Vanda is currently studying the efficacy of tasimelteon in Non-24-Hour Disorder in two PIII studies, SET and RESET, which are due to be completed by the end of 2012. RESET (NCT01430754) is a randomized withdrawal study designed to demonstrate the maintenance effect of 20mg tasimelteon. 20 totally blind individuals with no light perception and diagnosed as having a body clock period of greater than 24 hours, will be treated with tasimelteon for 3 months during a run-in phase. Patients who respond to treatment during the run-in phase, will be randomized either to receive placebo or to continue receiving tasimelteon for 2 months. Based on observations from 4 patients the company has reported that tasimelteon has been shown for the first time to reset the body clock and to align it to a constant 24-hour day [3].
04. Oct 12: In an open-label segment of the PIII RESET study totally blind patients with Non-24 were given a 20mg tasimelteon daily at bedtime for 6 weeks. The rhythms of melatonin and cortisol were assessed longitudinally in urine samples. The study found that entrainment of cortisol rhythm by tasimelteon was directly associated with entrainment of the melatonin rhythm. Vanda believes that the simultaneous entrainment of melatonin and cortisol suggests that tasimelteon can reset the master body clock in the suprachiasmatic nucleus (SCN) through binding to MT1 and MT2 melatonin receptors [4].
05. Dec 12: Results from the PIII SETS trial reported. In the randomized, double-masked study in 84 patients with Non-24, the primary endpoint of entrainment of the melatonin (aMT6s) rhythm was achieved vs placebo. Tasimelteon demonstrated significant improvements across a number of sleep and wake parameters including measures of total sleep time, nap duration, and timing of sleep. Improvements in the Non-24 Clinical Response Scale (N24CRS) and the Clinical Global Impression of Change (CGI-C) were also noted.Tasimelteon was found to be safe and well tolerated. Vanda expects to report top-line results from the second RESET in Q1 2013 [5].
06. Jan 13: Vanda announces positive PIII RESET results. The primary endpoint of the study was the maintenance of effect as measured by entrainment of the melatonin (aMT6s) rhythm - these occurred in 90% in the tasimelteon gp vs. 20% in the placebo gp (p=0.0026). Results for the secondary endpoints in the tasimelteon vs. placebo groups were maintenance of entrainment of the cortisol rhythm 80% vs. 20% (p=0.0118), LQ-nTST (total nighttime sleep in the worst 25% of nights; LS mean minutes) -6.6 vs. -73.8 (p=0.0233), UQ-dTSD (total daytime sleep duration in the worst 25% of days; LS mean minutes) -9.6 vs. 49.8 (p=0.0266) & MoST (midpoint of sleep timing from both nighttime and daytime sleep; LS mean minutes) 19.8 vs. -16.2 (p=0.0108) [6].
07. Jun 13: Vanda Pharmaceuticals Inc. presented additional data today at ENDO 2013, the Endocrine Society´s 95th Annual Meeting for the SET and RESET study [9].
08. Aug 15: Results of two PIII RCTs (SET and RESET) published in the Lancet [21].
09. Likely to be expensive; cost in US about $10,000 per month [20].

Evidence based evaluations

Hetlioz · Jet lag disorder

Information

Hetlioz
Licence extension / variation
Vanda Pharmaceuticals
Vanda Pharmaceuticals

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Melatonin agonist binding to two receptors, Mel1a (MT1R) and Mel1b (MT2R)
Jet lag, shift work and exposure to bright light at night result in desynchrony between the internal clock and the external light-dark cycle brought on by rapid travel across time zones or by working a non-standard schedule, and reduce melatonin levels [1].
Jet lag disorder
Oral

Hetlioz · Circadian rhythm disturbance in Smith-Magenis Syndrome

Information

Hetlioz
Licence extension / variation
Vanda Pharmaceuticals
Vanda Pharmaceuticals

Development and Regulatory status

None
None
Pre-registration (filed)

Category

Melatonin agonist binding to two receptors, Mel1a (MT1R) and Mel1b (MT2R)
Smith-Magenis syndrome (SMS) is rare: the accepted prevalence is about 1 in 25,000, however some sources suggest that many affected individuals are undiagnosed and the true prevalence may be nearer 1 in 15,000 [3]. Those affected frequently have sleep disturbance, which results in daytime sleepiness and night-time restlessness [3], and is due to an inverted melatonin circadian rhythm [4].
Circadian rhythm disturbance in Smith-Magenis Syndrome
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