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
May 19 · Vanda has yet to decide on UK launch plans [24].
May 17 · Launch in UK is planned but no date has yet been decided [23].
Aug 16 · Launched in Germany [22].
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].
Apr 15 · EU positive opinion for treatment of non-24-hour sleep-wake disorder (non-24) in totally blind adults [18].
Sep 14 · Vanda initiates the HELITOZAccess Named Patient Programme in the EU and Canada, where tasimelteon regulatory approvals are being sought [17].
Jun 14 · EU filing for the treatment of non-24-hour sleep-wake disorder in the blind accepted by the EMA [16].
Apr 14 · Launched in the US [15]
Feb 14 · Hetlioz has orphan-product designation in the US. It will be launched in the US in 2Q 14 [14].
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]
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].
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].
Aug 13 · Granted priority review in the US with a decision on approval expected by January 31, 2014 [10].
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]
Dec 12 · Vanda plans to file in the US in mid-2013 [5].
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].
Aug 10 · PIII study started [1]

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

Sep 15 · Likely to be expensive; cost in US about $10,000 per month [20].
Aug 15 · Results of two PIII RCTs (SET and RESET) published in the Lancet [21].
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].
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].
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].
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].
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].
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].
Jul 10 · 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].

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
Not approved
Feb 20 · Vanda says it is continuing to pursue approval of Hetlioz for jet lag disorder in the US. Details of how they are doing this, or any plans for EU/UK developement not reported [8].
Aug 19 · Vanda receives a Complete Response Letter (CRL) from the US FDA. The company has conducted a meeting with the US FDA to discuss the CRL in a Post Action meeting and is determining its next steps to resolve the issues outlined in the CRL [7].
Aug 19 · FDA approval decision currently expected in August 2019 [6].
Dec 18 · Filed in US [7].
Aug 18 · Vanda Pharmaceuticals announces intention to submit sNDA to the US FDA for Circadian rhythm sleep disorders (Jet lag disorder), by end 18 [5].

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

Trial or other data

Mar 18 · Positive results from PIII JET8 trial (n=318 healthy volunteers) announced of Hetlioz for jet lag disorder. Volunteers were put to sleep 8 hours before their usual bedtime (which was considered comparable to crossing 8 time zones). The primary endpoint was the amount of sleep time in the 1st two thirds of the night. Secondary endpoints were various sleep parameters, TST, LPS, WASO and next day alertness, KSS and VAS. The total sleep time benefit magnitude was 85 minutes’ improvement over placebo. It also showed improvements in next day alertness for KSS and VAS.[4]
Nov 17 · Results from the study of HETLIOZ for treatment of jet lag disorder after transmeridian travel (2102) are expected in Q4 2017. An 8-hour phase advance, simulated jet lag disorder study (3107) was initiated in Oct 17 and is expected to be fully enrolled by end of 2017. Results are expected in Q1 2018 [3].
Dec 15 · Vanda Pharmaceuticals initiates a PIII trial to evaluate the efficacy and safety of multiple oral doses of tasimelteon and matching placebo in travellers with jet lag disorder (EudraCT2015-003198-14; VP-VEC162-3106). The randomised, double-blind, parallel group study is enrolling approximately 400 patients in the UK and will be extending to France, Germany, the Netherlands and the US [2].

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)
Aug 20 · Filed in US with Priority Review status; a decision is expected by 1/12/20 [9].
Nov 19 · Vanda plans to file in the US in Q4 19 [8].
Mar 19 · No indication that further PIII trial has started [2].
May 16 · Vanda announce that a PIII trial will be started "in the second half of 2016" [1].

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
Oral

Trial or other data

Dec 18 · The primary endpoint of improvement in the 50% worst sleep quality was met in the proof-of-concept PII/III study (NCT02231008). [8].
Sep 18 · Enrolment completes in a PII/III trial in Circadian rhythm sleep disorders (Smith-Magenis Syndrome) [7].
Nov 17 · Enrollment in the Smith-Magenis Syndrome clinical study, which started in Q4 16, is ongoing. Results are expected in 2018 [6].
Sep 15 · Placebo-controlled "proof-of-concept" PII/III trial (NCT02231008) initiated to assess the effects of tasimelteon on sleep parameters in patients with SMS (estimated n=48); primary outcome is improvement in sleep parameters at 21 weeks and estimated primary completion date July 2017 [2].