Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Idorsia Pharmaceuticals Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany
Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned
Daridorexant is a dual orexin receptor antagonist, acting on both orexin 1 and orexin 2 receptors and equipotent on both. The orexin neuropeptides (orexin A and orexin B) act on orexin receptors to promote wakefulness. Daridorexant antagonises the activation of orexin receptors by the orexin neuropeptides and consequently decreases the wake drive, allowing sleep to occur, without altering the proportion of sleep stages (as assessed by electroencephalographic recording in rodents or polysomnography in patients with insomnia).
The efficacy of daridorexant was evaluated in two multicentre, randomised, double-blind, placebocontrolled, parallel-group, Phase 3 studies, Study 1 and Study 2, which were identical in design.
A total of 1854 subjects with insomnia disorder (dissatisfaction with sleep quantity or quality, for at least 3 months, with clinically significant distress or impairment in daytime functioning) were randomised to receive daridorexant or placebo once daily, in the evening, for 3 months. Study 1 randomised 930 subjects to daridorexant 50 mg (N=310), 25 mg (N=310), or placebo (N=310). Study 2 randomised 924 subjects to daridorexant 25 mg (N=309), 10 mg (N=307), or placebo (N=308). At baseline, the proportion of subjects with an Insomnia Severity Index (ISI) score between 8–14, 15–21, and 22–28, was 12%, 58%, and 30%, respectively.
At the end of the 3-month treatment period, both confirmatory studies included a 7-day placebo run-out period, after which subjects could enter a 9-month double-blind, placebo-controlled extension study (Study 3). A total of 576 subjects were treated with daridorexant for at least 6 months of cumulative treatment, including 331treated for at least 12 months.
In Study 1, subjects had a mean age of 55.4 years (range 18 to 88 years), with 39.1% of subjects ≥65 years of age, including 5.8% ≥75 years of age. The majority were female (67.1%).
In Study 2, subjects had a mean age of 56.7 years (range 19 to 85 years), with 39.3% of subjects ≥65 years of age, including 6.1% ≥75 years of age. The majority were female (69.0%).
Primary efficacy endpoints for both studies were the change from baseline to Month 1 and Month 3 in Latency to Persistent Sleep (LPS) and Wake After Sleep Onset (WASO), measured objectively by polysomnography in a sleep laboratory. LPS is a measure of sleep induction and WASO is a measure of sleep maintenance.
Secondary endpoints included in the statistical testing hierarchy with Type 1 error control were patient-reported Total Sleep Time (sTST), evaluated every morning at home using a Sleep Diary Questionnaire (SDQ), and patient-reported daytime functioning, assessed using the sleepiness domain of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), every evening at home. The IDSIQ total score, Alert/cognition, and Mood domain scores were also evaluated to complete the assessment of daytime functioning.
Across the two studies, the efficacy of daridorexant increased with increasing dose on objective (LPS, WASO) and subjective (sTST) sleep variables as well as on daytime functioning as assessed by IDSIQ scores, both at Month 1 and Month 3.
In Study 1, the 50 mg dose showed statistically significant (p<0.001) improvements compared to placebo on all primary and secondary endpoints. For the 25 mg dose, statistical significance was consistently achieved on WASO and sTST across both studies, and on LPS in Study 1. The 10 mg dose was not effective.
The efficacy of daridorexant was similar across subgroups based on age, sex, race and region.
Table 2. Efficacy on sleep variables and daytime functioning – Study 1:
| 50 mg N=310 | 25 mg N=310 | Placebo N=310 | ||
|---|---|---|---|---|
| WASO (wake after sleep onset, min): sleep maintenance, assessed objectively by PSG | ||||
| Baseline | Mean (SD) | 95 (38) | 98 (39) | 103 (41) |
| Month 1 | Mean (SD) | 65 (35) | 77 (42) | 92 (42) |
| Change from baseline LSM (95% CL) | -29 [-33, -25] | -18 [-22, -15] | -6 [-10, -2] | |
| Difference to placebo LSM (95% CL) | -23 [-28, -18] | -12 [-17, -7] | ||
| Month 3 | Mean (SD) | 65 (39) | 73 (40) | 87 (43) |
| Change from baseline LSM (95% CL) | -29 [-33, -25] | -23 [-27, -19] | -11 [-15, -7] | |
| Difference to placebo LSM (95% CL) | -18 [-24, -13] | -12 [-17, -6] | ||
| LPS (latency to persistent sleep, min): sleep onset, assessed objectively by PSG | ||||
| Baseline | Mean (SD) | 64 (37) | 67 (39) | 67 (40) |
| Month 1 | Mean (SD) | 34 (27) | 38 (32) | 46 (36) |
| Change from baseline LSM (95% CL) | -31 [-35, -28] | -28 [-32, -25] | -20 [-23, -17] | |
| Difference to placebo LSM (95% CL) | -11 [-16, -7] | -8 [-13, -4] | ||
| Month 3 | Mean (SD) | 30 (23) | 36 (34) | 43 (34) |
| Change from baseline LSM (95% CL) | -35 [-38, -31] | -31 [-34, -27] | -23 [-26, -20] | |
| Difference to placebo LSM (95% CL) | -12 [-16, -7] | -8 [-12, -3] | ||
| sTST (subjective total sleep time, min): patient-reported | ||||
| Baseline | Mean (SD) | 313 (58) | 310 (60) | 316 (53) |
| Month 1 | Mean (SD) | 358 (74) | 345 (66) | 338 (65) |
| Change from baseline LSM (95% CL) | 44 [38, 49] | 34 [29, 40] | 22 [16, 27] | |
| Difference to placebo LSM (95% CL) | 22 [14, 30] | 13 [5, 20] | ||
| Month 3 | Mean (SD) | 372 (79) | 358 (72) | 354 (73) |
| Change from baseline LSM (95% CL) | 58 [51, 64] | 48 [41, 54] | 38 [31, 44] | |
| Difference to placebo LSM (95% CL) | 20 [11, 29] | 10 [1, 19] | ||
| IDSIQ sleepiness domain score (daytime functioning): patient-reported | ||||
| Baseline | Mean (SD) | 22.5 (7.2) | 22.1 (6.9) | 22.3 (6.9) |
| Month 1 | Mean (SD) | 18.6 (7.8) | 19.4 (7.1) | 20.3 (6.9) |
| Change from baseline LSM (95% CL) | -3.8 [-4.3, -3.2] | -2.8 [-3.3, -2.2] | -2.0 [-2.6, -1.5] | |
| Difference to placebo LSM (95% CL) | -1.8 [-2.5, -1.0] | -0.8 [-1.5, 0.0] | ||
| Month 3 | Mean (SD) | 16.5 (8.1) | 17.3 (7.6) | 18.5 (7.8) |
| Change from baseline LSM (95% CL) | -5.7 [-6.4, -5.0] | -4.8 [-5.5, -4.1] | -3.8 [-4.5, -3.1] | |
| Difference to placebo LSM (95% CL) | -1.9 [-2.9, -0.9] | -1.0 [-2.0, 0.0] | ||
CL = confidence limits; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LSM = least squares mean; PSG = polysomnography; SD = standard deviation.
Table 3. Efficacy on sleep variables and daytime functioning – Study 2:
| 25 mg N=309 | Placebo N=308 | ||
|---|---|---|---|
| WASO (wake after sleep onset, min): sleep maintenance, assessed objectively by PSG | |||
| Baseline | Mean (SD) | 106 (49) | 108 (49) |
| Month 1 | Mean (SD) | 80 (44) | 93 (50) |
| Change from baseline LSM (95% CL) | -24 [-28, -20] | -13 [-17, -8] | |
| Difference to placebo LSM (95% CL) | -12 [-18, -6] | ||
| Month 3 | Mean (SD) | 80 (49) | 91 (47) |
| Change from baseline LSM (95% CL) | -24 [-29, -19] | -14 [-19, -9] | |
| Difference to placebo LSM (95% CL) | -10 [-17, -4] | ||
| LPS (latency to persistent sleep, min): sleep onset, assessed objectively by PSG | |||
| Baseline | Mean (SD) | 69 (41) | 72 (46) |
| Month 1 | Mean (SD) | 42 (39) | 50 (40) |
| Change from baseline LSM (95% CL) | -26 [-31, -22] | -20 [-24, -16] | |
| Difference to placebo LSM (95% CL) | -6 [-12, -1] | ||
| Month 3 | Mean (SD) | 39 (37) | 49 (46) |
| Change from baseline LSM (95% CL) | -29 [-33, -24] | -20 [-24, -15] | |
| Difference to placebo LSM (95% CL) | -9 [-15, -3] | ||
| sTST (subjective total sleep time, min): patient-reported | |||
| Baseline | Mean (SD) | 308 (53) | 308 (52) |
| Month 1 | Mean (SD) | 353 (67) | 336 (63) |
| Change from baseline LSM (95% CL) | 44 [38, 49] | 28 [22, 33] | |
| Difference to placebo LSM (95% CL) | 16 [8, 24] | ||
| Month 3 | Mean (SD) | 365 (70) | 347 (65) |
| Change from baseline LSM (95% CL) | 56 [50, 63] | 37 [31, 43] | |
| Difference to placebo LSM (95% CL) | 19 [10, 28] | ||
| IDSIQ sleepiness domain score (daytime functioning): patient-reported | |||
| Baseline | Mean (SD) | 22.2 (6.2) | 22.6 (5.8) |
| Month 1 | Mean (SD) | 18.7 (6.5) | 19.8 (6.3) |
| Change from baseline LSM (95% CL) | -3,5 [-4.1, -2.9] | -2.8 [-3.3, -2.2] | |
| Difference to placebo LSM (95% CL) | -0.8 [-1,6, 0.1] | ||
| Month 3 | Mean (SD) | 17.0 (7.0) | 18.4 (6.6) |
| Change from baseline LSM (95% CL) | -5.3 [-6.0, -4.6] | -4.0 [-4.7, -3.3] | |
| Difference to placebo LSM (95% CL) | -1.3 [-2.2, -0.3] | ||
CL = confidence limits; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; LSM = least squares mean; PSG = polysomnography; SD = standard deviation.
The potential for rebound insomnia was assessed during the placebo run-out period after 3 months of treatment with daridorexant in Study 1 and Study 2, looking at the change from baseline to the run-out period in LPS, WASO and sTST. At the recommended dose of 50 mg, for all three endpoints, the mean values at run-out were improved compared to baseline (-15, -3 and 43 min for LPS, WASO and sTST, respectively), indicating that no sign of rebound insomnia was observed upon treatment discontinuation.
The European Medicines Agency has deferred the obligation to submit the results of studies with daridorexant in one or more subsets of the paediatric population in insomnia (see section 4.2 for information on paediatric use).
Daridorexant is rapidly absorbed following oral administration and reaches peak plasma concentrations within 1–2 h. At an oral dose of 100 mg, daridorexant has an absolute bioavailability of 62%.
Daridorexant plasma exposure is dose proportional between 25 and 50 mg.
In healthy subjects, food did not affect total exposure. The tmax of 50 mg daridorexant was delayed by 1.3 h and Cmax decreased by 16% following administration of a high-fat and high-calorie meal.
Daridorexant has a volume of distribution of 31 L. Daridorexant is extensively bound (99.7%) to plasma proteins, mostly to albumin and to a lower extent to α-acid glycoprotein. The blood to plasma ratio is 0.64.
Daridorexant undergoes extensive metabolism and is primarily metabolised by CYP3A4 (89%). Other CYP enzymes are not of clinical relevance and individually contribute to less than 3% of metabolic clearance. None of the major human metabolites (M1, M3, and M10) contribute to the pharmacological effect of the medicinal product.
Daridorexant inhibits several CYP enzymes in vitro. The strongest inhibition was seen on CYP3A4 with a Ki of 4.6–4.8 µM (see section 4.5). Inhibition of CYP2C8, CYP2C9, and CYP2C19 was less pronounced, with IC50 values in the range of 8.2–19 µM. Daridorexant induces CYP3A4 mRNA expression in human hepatocytes with an EC50 of 2.3 µM and, to a lesser extent, CYP2C9 and CYP2B6. Up-regulation of all CYP enzymes is mediated via activation of the PXR receptor with an EC50 of 3 µM. Daridorexant does not induce CYP1A2.
Daridorexant inhibits various transporters in vitro and had the strongest inhibitory effect on BCRP with an IC50 of 3.0 µM (see section 4.5). Inhibition of other transporters including OATP, OAT3, OCT1, MATE-2K, MATE1, and P-gp/MDR1 was less pronounced, with IC50 values ranging from 8.4–71 µM.
The primary route of excretion is via faeces (approximately 57%), followed by urine (approximately 28%). Only traces of parent compound were found in urine and faeces.
The terminal half-life of daridorexant is approximately 8 hours.
The PK profile of daridorexant following multiple-dose administration showed similar PK parameters to those observed after single-dose administration. No accumulation was observed.
No clinically significant differences in the PK of daridorexant were detected based on age, sex, race, or body size. Limited PK data are available in patients older than 75 years.
Following administration of a single dose of 25 mg daridorexant, subjects with mild hepatic impairment (Child-Pugh score 5–6) had a similar exposure to unbound daridorexant compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7–9), exposure to unbound daridorexant (AUC) and half-life increased by 1.6 times and 2.1 times, respectively, compared to healthy subjects.
Based on these results, a dose adjustment is recommended in patients with moderate hepatic impairment (see section 4.2).
In patients with severe hepatic impairment (Child-Pugh score ≥ 10), daridorexant has not been studied and is not recommended.
Following administration of a single dose of 25 mg, the PK parameters of daridorexant were similar in subjects with severe renal impairment compared to healthy subjects.
Based on these results, daridorexant can be administered to patients with any degree of renal function impairment without the need for dose adjustment.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Daridorexant also showed no signs indicative of abuse potential or physical dependence.
No adverse effects were observed in repeat-dose toxicity studies in rats and dogs at exposures that are 72 times and 14 times, respectively, the human exposure at the maximum recommended dose of 50 mg/day.
In dogs under positive stimulation at play, episodes of sudden muscle weakness, reminiscent of cataplexy, were observed as exaggerated pharmacological effects of daridorexant from Week 7 onwards and did not occur after treatment cessation. An overall no-observed-effect level was established at exposures that are 45 times (females) and 78 times (males) the human exposure at 50 mg/day for the free fraction.
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