Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Vanda Pharmaceuticals Netherlands B.V., Basisweg 10, 1043 AP Amsterdam, The Netherlands
Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists
ATC code: N05CH03
Tasimelteon is a circadian regulator that resets the master body clock in the suprachiasmatic nucleus (SCN). Tasimelteon acts as a Dual Melatonin Receptor Agonist (DMRA) with selective agonist activity at the MT1 and MT2 receptors. These receptors are thought to be involved in the control of circadian rhythms. The master body clock regulates the circadian rhythms of hormones including melatonin and cortisol and aligns/synchronises the physiological processes of the sleep-wake cycle and metabolic and cardiovascular homeostasis.
Tasimelteon functions as a DMRA at the MT1 and MT2 receptors. Tasimelteon exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The most abundant metabolites of tasimelteon have less than one-tenth of the binding affinity of the parent molecule for both the MT1 and MT2 receptors.
Tasimelteon and its most abundant metabolites have no appreciable affinity for more than 160 other pharmacologically relevant receptors. This includes the GABA receptor complex, the binding site for sedative hypnotics, and receptors that bind neuropeptides, cytokines, serotonin, noradrenaline, acetylcholine, and opiates.
The effectiveness of tasimelteon in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomised, double-masked, placebo-controlled, multicentre, parallel-group studies (SET and RESET) in totally blind patients with Non-24.
In SET, 84 patients with Non-24 (median age 54 years) were randomised to receive tasimelteon 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months.
RESET was a randomised withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of tasimelteon after 12-weeks. Patients were treated for approximately 12 weeks with tasimelteon 20 mg one hour prior to bedtime, at the same time every night. Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomised to receive placebo or continue daily treatment with tasimelteon 20 mg for 8 weeks.
SET and RESET assessed entrainment of the master body clock as measured by aMT6s and cortisol. Both studies demonstrated the ability of tasimelteon to entrain the master body clock in patients with Non-24 and RESET demonstrated that continued daily dosing of tasimelteon is necessary to maintain entrainment.
In SET, tasimelteon entrained circadian rhythms at month 1 at a significantly higher rate than placebo as measured by aMT6s and cortisol (20% vs. 2.6 % and 17.5% vs 2.6% respectively). Analyses of entrainment at month 7 in a subset of patients demonstrated that 59% of tasimelteon-treated patients entrained by month 7 indicating that response to treatment may take weeks or months for some patients to respond. RESET demonstrated the maintenance of entrainment with tasimelteon treatment compared to placebo withdrawal (aMT6s: 90% vs. 20% and cortisol: 80% vs. 20%).
The effectiveness of tasimelteon in the treatment of clinical symptoms, including the circadian sleep-wake cycle and clinical global functioning in patients with Non-24 was established in SET and RESET (Table 3). A composite scale of 4 measures of duration and timing of nighttime and daytime sleep and global functioning was used to evaluate clinical response in SET. Entrainment plus a score ≥3 on this scale, called Non-24 Clinical Response Scale (N24CRS) was required to be classified as a clinical responder. The components of the scale can be found in Table 2.
Table 2. Non-24 Scale of Clinical Response:
| Assessment | Threshold of Response |
|---|---|
| Nighttime sleep on 25% most symptomatic nights | ≥45 minutes increase in average nighttime sleep duration |
| Daytime sleep on 25% most symptomatic days | ≥45 minutes increase in average nighttime sleep duration |
| Timing of sleep | ≥30 minutes increase and a standard deviation ≤2 hours during double-masked phase |
| CGI-C | ≤2.0 from the average of Day 112 and Day 183 compared to baseline |
SET and RESET evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries. During SET, patient diaries were recorded for an average of 88 days during screening and 133 days during randomisation. During RESET, patient diaries were recorded for an average of 57 days during the run-in phase and 59 days during the randomised-withdrawal phase.
Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. In SET, patients in the tasimelteon group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively. The average timing of sleep relative to an individual’s desired period for consolidated sleep over at least one circadian period was assessed. Treatment with tasimelteon resulted in a significant improvement, compared with placebo, for all of these endpoints in SET and RESET (see Table 3).
Table 3. Effects of Tasimelteon 20 mg Treatment on Clinical Response in Non-24:
| Tasimelteon 20 mg | Placebo | % Difference | p-value | |
|---|---|---|---|---|
| SET Study | ||||
| Clinical response (Entrainment + N24CRS ≥3)1 | 9/38 (23.7) | 0/34 (0.0) | 23.7 | 0.0028 |
| N24CRS ≥32 | 11/38 (28.9) | 1/34 (2.9) | 26.0 | 0.0031 |
| N24CRS ≥22 | 22/38 (57.9) | 7/34 (20.6) | 37.3 | 0.0014 |
| Nighttime sleep on 25% most symptomatic nights (minutes)3 | 56.80 | 17.08 | 39.71 | 0.0055 |
| Daytime sleep time on 25% most symptomatic days (minutes)3,4 | -46.48 | -17.87 | -28.61 | 0.0050 |
| ≥45 min improvement in both nighttime and daytime sleep (%)5 | 31.6 | 8.8 | 22.8 | 0.0177 |
| Timing of sleep (minutes)1,3 | 35.00 | 14.48 | 20.52 | 0.0123 |
| RESET Study | ||||
| Nighttime sleep on 25% most symptomatic nights (minutes)3 | -6.74 | -73.74 | 67.00 | 0.0233 |
| Daytime sleep time on 25% most symptomatic days (minutes)3,4 | -9.31 | 49.95 | -59.25 | 0.0266 |
| Timing of sleep (minutes)1,3 | 19.99 | -16.05 | 36.04 | 0.0108 |
1 Higher numbers indicates improvement
2 Sensitivity Analysis
3 P-value was based on analysis of covariance model, units are LS mean minutes
4 Lower numbers indicates improvement
5 Post-hoc analysis
Patients treated with tasimelteon experienced an overall improvement in clinical global functioning (CGI- C = 2.6) as compared to patients treated with placebo who showed no improvement status (CGI-C = 3.4) compared to the severity of Non-24 at baseline (LS mean difference = -0.8; p=0.0093) (Table 4). The effectiveness of tasimelteon to improve clinical global functioning was evaluated in SET. The Clinical Global Impression of Change (CGI-C) is a reflection of the general social, occupational, and health functioning of the patient and is evaluated on a 7-point scale, centered at No Change (4), that investigators used to rate the patients' improvement from baseline in symptoms of global functioning. It was rated as: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse.
Table 4. Clinical Global Functioning in Non-24 Patients:
| Tasimelteon 20 mg | Placebo | p-value | |
|---|---|---|---|
| CGI-C (LS mean) | 2.6 | 3.4 | 0.0093 |
See section 4.8 for safety information.
The European Medicines Agency has deferred the obligation to submit the results of studies with HETLIOZ in one or more subsets of the paediatric population who are totally blind with Non-24. See section 4.2 for information on paediatric use.
The pharmacokinetics of tasimelteon is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of tasimelteon and its metabolites did not change with repeated daily dosing.
The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 hours after fasted oral administration. The mean absolute oral bioavailability of tasimelteon is 38%.
When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when administered in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, tasimelteon should be taken without food; if patients eat a high-fat meal, it is recommended to wait at least 2 hours before taking tasimelteon.
The apparent oral volume of distribution at steady state of tasimelteon in young healthy subjects is approximately 59 – 126 L. At therapeutic concentrations, tasimelteon is about 88.6 – 90.1% bound to proteins.
Tasimelteon is extensively metabolised. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 (35.4%) and CYP3A4 (24.3%) are the major enzymes identified to play a role in the metabolism of tasimelteon. CYP2C9 (18.8%) and CYP2C19 (15.1%) also contribute to the metabolism of tasimelteon. Tasimelteon clearance does not appear to be affected by polymorphisms in these enzymes.
Phenolic glucuronidation is the major phase II metabolic route.
Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon.
Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in faeces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. The mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2.
Repeated once daily dosing with tasimelteon does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon.
In elderly subjects, tasimelteon exposure increased by approximately two-fold compared to non-elderly adults. Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful and dose adjustment is not recommended.
The mean overall exposure of tasimelteon was approximately 1.6-fold greater in female than in male subjects. Due to the overall inter-subject variability of tasimelteon, this increase is not clinically meaningful and dose adjustment is not recommended.
Race does not affect apparent clearance of tasimelteon.
The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), 8 subjects with moderate hepatic impairment (Child-Pugh Score ≥7 and ≤9 points), and 13 healthy matched controls. Tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. Therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. Tasimelteon has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore caution is recommended when prescribing HETLIOZ to patients with severe hepatic impairment.
The pharmacokinetic profile of a 20 mg dose of tasimelteon was compared among 8 subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤29 mL/min/1.73m²), 8 subjects with end-stage renal disease (ESRD) (GFR <15 mL/min/1.73m²) requiring hemodialysis, and 16 healthy matched controls. There was no apparent relationship between tasimelteon CL/F and renal function, as measured by either estimated creatinine clearance or eGFR. Subjects with severe renal impairment had a 30% lower CL/F clearance than match controls; however, when variability is taken into account, the different was not significant. No dose adjustment is necessary for patients with renal impairment.
Tasimelteon exposure decreased by approximately 40% in smokers, compared to non-smokers (see section 4.5). The patient should be instructed to cease or reduce smoking while taking tasimelteon.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In pregnant rats administered tasimelteon during the period of organogenesis, there were no effects on embryofoetal development. In pregnant rabbits administered tasimelteon during the period of organogenesis, embryolethality and embryofoetal toxicity (reduced foetal body weight and delayed ossification) were observed at the highest dose tested (200 mg/kg/day).
Oral administration of tasimelteon to rats throughout organogenesis and lactation resulted in persistent reductions in body weight, delayed sexual maturation and physical development, neurobehavioural impairment in offspring at the highest dose tested, andreduced body weight in offspring at the mid-dose tested. The no effect dose (50 mg/kg/day) is approximately 25 times the RHD on a mg/m² basis.
No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 times the RHD of 20 mg/day, on a mg/m² basis. In rats, the incidence of liver tumours was increased in males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumours of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased at 250 mg/kg/day. There was no increase in tumours at the lowest dose tested in rats, which is approximately 10 times the recommended human doseon a mg/m² basis.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.