tasimelteon and Blindness

Non-24-h sleep-wake disorder (non-24) is a circadian rhythm disorder occurring in 55-70% of totally blind individuals (those lacking conscious light perception) in which the 24-h biological clock (central, hypothalamic, circadian pacemaker) is no longer synchronized, or entrained, to the 24-h day. Instead, the overt rhythms controlled by the biological clock gradually shift progressively earlier or later (free run) in accordance with the clock's near-24-h period, resulting in a recurrent pattern of daytime hypersomnolence and night-time insomnia. Orally administered melatonin and the melatonin agonist tasimelteon have been shown to entrain (synchronize) the circadian clock, resulting in improvements in night-time sleep and daytime alertness. We review the basic principles of circadian rhythms necessary to understand and treat non-24. The time of melatonin or tasimelteon administration must be considered carefully. For most individuals, those with circadian periods longer than 24 h, low-dose melatonin should be administered about 6 h before the desired bedtime, while in a minority, those with circadian periods shorter than 24 h (more commonly female individuals and African-Americans), melatonin should be administered at the desired wake time. Small doses (e.g., 0.5 mg of melatonin) that are not soporific would thus be preferable. Administration of melatonin or tasimelteon at bedtime will entrain individuals with non-24 but at an abnormally late time, resulting in continued problems with sleep and alertness. To date, tasimelteon has only been administered 1 h before the target bedtime in patients with non-24. Issues of cost, dose accuracy, and purity may figure into the decision of whether tasimelteon or melatonin is chosen to treat non-24. However, there are no head-to-head studies comparing efficacy, and studies to date show comparable rates of treatment success (entrainment).

Topics: Benzofurans; Blindness; Circadian Clocks; Cyclopropanes; Humans; Melatonin; Sleep Wake Disorders

Tasimelteon (Hetlioz®), a melatonin receptor agonist, is the first, and, at the time of the publication, the only drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-24-hour sleep-wake disorder (non-24). This circadian rhythm disorder occurs most commonly in blind individuals without light perception, and it results from their inability to entrain to the 24-hour photoperiod, although the indication does not specify a particular patient population. Non-24 is characterized by a persistent cycle of nighttime insomnia and daytime sleepiness, alternating with asymptomatic periods depending on an individual's degree of circadian rhythm synchronization with the photoperiod at any particular time. Phase II clinical trials in healthy individuals confirmed the circadian phase-shifting potential of tasimelteon. Phase III trials in totally blind subjects diagnosed with non-24 demonstrated the efficacy of tasimelteon in reducing both nighttime wakefulness and daytime napping. Physiologic monitoring revealed that tasimelteon resulted in a higher proportion of individuals becoming entrained to the 24-hour cycle compared with placebo. Safety assessments indicated that tasimelteon is well tolerated, with the most common adverse events being headache, alanine aminotransferase elevation, nightmares or unusual dreams, and upper respiratory or urinary tract infections. Tasimelteon is available as a capsule in a single 20-mg dose and it must be obtained through Vanda Pharmaceutical's HetliozSolutions program with dispensing through a specialty pharmacy. Safety studies in blind individuals diagnosed with non-24 are ongoing and a future clinical trial with Smith-Magenis syndrome patients is planned.

Topics: Activity Cycles; Animals; Benzofurans; Blindness; Cyclopropanes; Drug Interactions; Humans; Receptors, Melatonin; Signal Transduction; Sleep; Sleep Disorders, Circadian Rhythm; Time Factors; Treatment Outcome; Wakefulness

Many individuals with total blindness can develop a circadian rhythm disorder-called non-24 sleep wake syndrome-because they cannot detect light to resynchronize their sleep-wake cycles. A new melatonin 1 and melatonin 2 agonist tasimelteon improves sleep in these patients, resetting their circadian sleep-wake clocks.

Topics: Benzofurans; Blindness; Cyclopropanes; Humans; Receptors, Melatonin; Sleep Disorders, Circadian Rhythm

Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist.. We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18-75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov, numbers NCT01163032 and NCT01430754.. Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2-31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4-39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26·4-100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]).. Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements.. Vanda Pharmaceuticals.

Topics: Benzofurans; Blindness; Circadian Rhythm; Cyclopropanes; Double-Blind Method; Female; Humans; Male; Middle Aged; Receptors, Melatonin; Sleep Disorders, Circadian Rhythm; Treatment Outcome

We present a totally blind adolescent with refractory insomnia due to a combination of Non-24 hour sleep-wake disorder and restless leg syndrome that was successfully treated with tasimelteon, iron replacement, and gabapentin. To our knowledge, this is the first published report of treatment of N24 with tasimelteon in an adolescent. In addition, this case highlights the importance of recognizing and treating multifactorial causes of insomnia.

Topics: Adolescent; Benzofurans; Blindness; Cyclopropanes; Drug Resistance; Drug Therapy, Combination; Female; Gabapentin; Humans; Iron; Restless Legs Syndrome; Sleep Disorders, Circadian Rhythm; Sleep Initiation and Maintenance Disorders

Topics: Benzofurans; Blindness; Circadian Rhythm; Cyclopropanes; Cytochrome P-450 CYP1A2; Humans; Receptors, Melatonin; Sleep Wake Disorders