Medical Uses of Daridorexant

Abstract

The present invention relates to daridorexant: Formula (I) or a pharmaceutically acceptable salt thereof, particularly the hydrochloride salt, for use in a method for the treatment of sleep disorders, particularly insomnia, wherein daridorexant improves daytime activity and particularly reduces daytime sleepiness associated with such sleep disorders. [Case 1] TIFF2023521492000005.tif72146

Description

[Technical Field]

[0001] The present invention relates to daridorexant, [(S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-pyrrolidin-1-yl]-(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone (also referred to as ACT-541468):

[0002] [ka]

[0003] Or particularly of a pharmaceutically acceptable salt thereof such as the hydrochloride salt; particularly for use in the treatment of sleep disorders such as insomnia; wherein daridrexant improves daytime performance and particularly reduces daytime sleepiness associated with such sleep disorders. [Background technology]

[0004] The preparation of daridorexant and its pharmaceutical use are described in WO 2013 / 182972 and WO 2015 / 083094. A crystalline salt form of daridorexant is disclosed in WO 2015 / 083071; a crystalline form of daridorexant in free base form is disclosed in WO 2015 / 083070. In rats, for example, daridorexant has been shown to cross the blood-brain barrier and promote sleep, which is characterized by pharmacological effects on active wake, home cage activity, NREM sleep, and REM sleep. Daridorexant has also been reported to have activity in animal models of agitation associated with sundowning / agitation in dementia (WO 2015 / 083094). In addition, many literature studies have reported on the pharmacological actions of orexin receptor antagonists with different structures that may be relevant to mental health diseases or disorders associated with orexin dysfunction (e.g., sleep disorders, anxiety disorders, addictive disorders, cognitive dysfunction, mood disorders, agitation or appetite disorders in dementia, etc.).

[0005] (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5): American Psychiatric Association Insomnia (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing; 2013) is a common problem. Population-based epidemiological studies suggest that more than 30% of the general population complain of insomnia, and approximately 10% of the general population complain of insomnia with associated symptoms of distress or daytime dysfunction consistent with a diagnosis of insomnia disorder (NIH Consensus and State-of-the-Science Statements, 2005 Jun;13-15;22(2):1-30; Roth J Clin Sleep Med. 2007;3 Suppl 5:S7-10). Symptoms of insomnia (difficulty falling asleep, early morning awakening, and lack of satisfaction with sleep) increase with age. Age-related factors, as well as factors unrelated to age itself, such as depressed mood, respiratory symptoms, poor subjective health status, and physical disability, are associated with decreased sleep ability [Ohayon et al., J Am Geriatr Soc. 2001;49(4):360-366]. Insomnia disorders result in difficulty falling asleep or staying asleep and are characterized by multiple or prolonged awakenings during sleep periods or early awakenings. Difficulty staying asleep is the most common problem for insomnia patients, occurring in approximately two-thirds of patients [Neubauer, Int Rev Psychiatry. 2014;26(2):214-24]. Research has shown that the most common symptom is a combination of difficulty falling asleep and staying asleep [Hohagen et al., Sleep. 1994;17(6):551-4]. Older patients tend to suffer from chronic insomnia, which is characterized by difficulty staying asleep rather than difficulty falling asleep [McCall Prim Care Companion J Clin Psychiatry.2004;6(1):9-20].

[0006] Insomnia is associated with cognitive impairment, daytime fatigue, increased risk of accidents, and interpersonal difficulties. Insomnia increases healthcare utilization, correlates with chronic health problems and perceptions of poor health, and may even lead to falls in elderly subjects (see, e.g., Ancoli-Israel and Roth, Sleep. 1999;22 Suppl 2:S354-58; Zammit et al., Sleep. 1999;22 Suppl 2:S379-85; Fortier-Brochu and Morin, Sleep. 2014;37(11):1787-98; McCall Prim Care Companion J Clin Psychiatry. 2004;6(1):9-20). Extensive research has demonstrated an association between insomnia and psychiatric disorders, specifically depression, anxiety, and other important mental health conditions [Ford and Kamerow, JAMA. 1989;262(11):1479-84; Benca et al., J Clin Psychiatry. 2004;65 Suppl 8:26-35].

[0007] Current standard of care encompasses non-pharmacological and pharmacologic treatments [Schutte-Rodin et al., J Clin Sleep Med. 2008;4:487-504]. Non-pharmacological (psychological and behavioral) standard treatments for insomnia include various therapeutic approaches, such as cognitive behavioral therapy (CBT), stimulus control, and relaxation training. Sleep hygiene treatments are often added to these treatment modalities. Prescription hypnotics (hypnotics) indicated for the treatment of insomnia include benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, melatonin agonists, orexin receptor antagonists, suvorexant, and low-dose doxepin.

[0008] Benzodiazepines belong to a class of drugs that bind to many gamma-aminobutyric acid (GABA) type A receptor subtypes [Lieberman Prim Care Companion J Clin Psychiatry. 2007;9(1):25-31]. This class of medications, including flurazepam, temazepam, triazolam, estazolam, and quazepam, was previously commonly prescribed for insomnia. While the efficacy of these medications is well documented, their usefulness is limited by adverse effects such as daytime sedation (e.g., morning or next-day persistence), cognitive impairment (including anterograde amnesia), motor dyscoordination, abuse liability, and dependence [Holbrook et al., CMAJ 2000;162(2):225-33; Buscemi et al., J Gen Intern Med. 2007;22(9):1335-50]. Benzodiazepines also alter sleep architecture: they may prolong stage 2 sleep and slightly decrease the relative amount of rapid eye movement (REM) sleep [Drugs for insomnia. Treat Guidel Med Lett. 2009;7:23-6]. Their use has been associated with tolerance development and rebound insomnia upon withdrawal [Kales et al., Science. 1978;201(4360):1039-41; Petursson et al., Br J Addict. 1981;76(2):133-45].

[0009] Non-benzodiazepine benzodiazepine receptor agonists have more targeted effects on one or more GABA type A receptor subtypes, but the availability of these treatments varies widely by region. Zolpidem, controlled-release zolpidem (CR), and zaleplon have affinity for the alpha-1 receptor subtype, while eszopiclone has affinity for the alpha-2 and -3 receptor subtypes [Nutt J Clin Sleep Med. 2006;2(2):Suppl S7-11; see also Hair et al., CNS Drugs (2008), 22:975-978]. All of these medications decrease the latency to sleep onset, but zolpidem CR and eszopiclone have also been shown to reduce wake-after-sleep onset (WASO) and improve sleep maintenance (Ambien® USPI, Lunesta® USPI). Perhaps due to their receptor selectivity, these medications have less of an effect on sleep architecture, although this group of medications can have adverse effects similar to benzodiazepines. In 2007, the US Food and Drug Administration (USFDA) The US Food and Drug Administration (FDA) has required all manufacturers of hypnotic products to include stronger warnings about potential risks in their product labels. These risks include severe allergic reactions (i.e., anaphylaxis) and complex sleep-related behaviors, which may include sleep-driving. [US Food and Drug Administration (US) Requests Label Change for All Sleep Disorder Drug Products. Available at: https: / / www.fdanews.com / articles / 91163-fda-requests-label-change-for-sleep-disorder-drugs]. Nevertheless, hypnotics, including triazoles, zaleplon, zolpidem, and eszopiclone, are proposed as first-line medications for inducing sleep, compared with other drug classes, including, for example, orexin receptor antagonists (suvorexant) (Pagel et al., Sleep Science and Practice (2018):2-5).

[0010] Sleep medication use increases with age, with the elderly being the most prevalent [Ohayon et al., Sleep Med.2002;3(2):115-20;Ohayon et al., Sleep Med. 2010;11(10):1010-8]. Despite the increased risk of falls, non-benzodiazepine benzodiazepine receptor agonists and generic antidepressants are among the most prescribed classes of medications for elderly patients in the United States.

[0011] Newer hypnotic drugs that do not act on GABA receptors are being developed. Ramelteon, a melatonin receptor agonist, is approved for insomnia in the United States and Japan but not in Europe. Ramelteon reduces sleep latency and increases total sleep time (TST), but has no effect on WASO [Kuriyama et al., Sleep Med. 2014;15(4):385-92], making it an inappropriate treatment for people with sleep maintenance problems [Simpson and Curran, Drugs. 2008;68(13):1901-19]. Ramelteon is generally considered to have no next-day residual effects, withdrawal, or rebound insomnia and does not appear to be associated with abuse liability. However, Mets et al. (Sleep (2011), 34(10):1327-1334) disclosed a study in which both ramelteon and zopiclone were found to have significant next-day residual effects on psychomotor function, memory, performance, and mood.

[0012] Suvorexant is an oral dual orexin receptor antagonist (DORA) approved, for example, in the United States, Japan, and Australia, for the treatment of insomnia characterized by difficulty falling asleep and / or staying asleep. Suvorexant is contraindicated in patients with narcolepsy. Next-day effects, including impaired driving performance, have been reported at 20 mg [Belsomra® USPI]. The next-day residual effects are attributed to the long half-life of suvorexant (t 1 / 2= 12 hours] [Citrome Int J Clin Pract. 2014;68(12):1429-41]. Rebound insomnia or withdrawal symptoms upon drug discontinuation were not observed in clinical trials [Herring et al., Biol Psychiatry. 2016;79(2):136-48]. In the United States, the package insert for suvorexant (BELSOMRA®) contains the following warnings and precautions typical of drugs indicated for the treatment of insomnia: "CNS Depressant Effects and Daytime Impairment: Risk of decreased alertness and motor coordination (including impaired driving performance); risk increases with dose; patients taking 20 mg should be careful about driving and other activities requiring complete mental alertness the next day," and more specifically: "BELSOMRA® is a central nervous system (CNS) depressant that, when used as prescribed, causes decreased daytime alertness."

[0013] Similarly, lemborexant (DAYVIGO®), another DORA, was approved in the U.S. with a package insert that includes the following similar warnings and precautions: "CNS depressant effects and daytime dysfunction: impaired attention and motor coordination (including morning impairment). Risk increases with dose and with concomitant use of other central nervous system (CNS) depressants. Patients taking DAYVIGO® 10 mg should be cautious about next-day driving and other activities requiring full alertness." WO2016 / 063995 / US10,188,652 claims the following: "A method for treating insomnia comprising orally administering a dosage form having a therapeutically effective amount of [lemborexant], wherein the therapeutically effective amount is a single daily dose ranging from about 2.5 mg to about 10 mg, and wherein, after administration to a human subject, the single daily dose achieves a mean Cmax of about 3.0 ng / ml to about 7.2 ng / ml per mg of [lemborexant]." During prosecution of this application at the USPTO, the USPTO stated, "[...] this application contains a patent application showing that oral administration to humans of a single daily dose ranging from about 2.5 mg to about 10 mg induces rapid onset of sleep without causing next-day drowsiness or impaired performance." The data includes data from Examples 3-5. Indeed, it was stated that "a dose of 2.5 mg or more of [lemborexant] was required to effectively induce sleep onset (see paragraph

[0242] ), and at doses above 10 mg, patients experienced significantly increased next-day sleepiness (see paragraph

[0244] )." Therefore, it is believed that increasing the dose of lemborexant (>10 mg) will significantly increase next-day sleepiness, and for this compound to effectively induce sleep onset without causing next-day sleepiness or functional impairment, a narrow dose range of between 2.5 mg and 10 mg per day should be selected.

[0014] Warnings and precautions regarding CNS depressant effects and daytime impairment generally derive from the overall assessment of the respective health authorities in light of the results of clinical trials in patients and routine safety studies in healthy volunteers; these studies (e.g., Phase 2 clinical trials or safety studies) may include the study of supra-therapeutic doses (i.e., doses higher than those ultimately approved for treatment by the respective health authorities).

[0015] In Phase 3 clinical trials of suvorexant (NCT01097616, NCT01097629) and lemborexant (NCT02783729, NCT02952820) in patients with insomnia, the effect of treatment with the compounds was observed on an exploratory basis (i.e., not in the form of a validated clinical endpoint) in a post-hoc analysis as measured by the Insomnia Severity Score (ISI(©)) [Herring et al., Sleep Medicine 56(2019)219-223:https: / / doi.org / 10.1016 / j.sleep.2018.09.010; Rosenberg et al., JAMA Network Open.2019;2(12):e1918254.doi:10.1001 / jamanetworkopen.2019.18254]. The Insomnia Severity Index (ISI©) (Morin et al.; SLEEP 2011;34(5):601-608) is a validated, brief instrument designed to assess the severity of both the nocturnal and daytime phases of insomnia overall. It assesses a patient's insomnia severity by scoring difficulty in falling asleep and staying asleep, as well as the severity of insomnia-related impairments on daytime functioning. Ratings are made on a 5-point scale (0-4), with a total score obtained by summing seven rated dimensions that measure the subject's perception of their insomnia. A score of 15-21 indicates moderate insomnia, and a score of 22-28 indicates severe insomnia. An ISI (copyright) total score of less than 10 indicates minimal to no improvement in the subject's subjectively rated insomnia symptoms, daytime dysfunction, and quality of life [Morin et al., J Consult Clin Psychol. 1993;61(1):137-46; Scharf et al., Sleep. 2007;30(6):743-52; Morin et al., SLEEP 2011;34(5):601-608].

[0016] Lemborexant was also assessed on an exploratory basis for a more daytime-related ISI score, i.e., a subscore of only items 4-7 (Roth et al., Poster presented at the 33rd Annual Meeting of the Associated Professional Sleep Societies (APSS); June 8-12, 2019; San Antonio, Texas). ISI (Copyright) items 4-7 assess the following questions: 4. How satisfied / dissatisfied are you with your current sleep patterns? 5. To what extent do you think others are aware of your sleep problems in relation to your reduced quality of life? 6. How worried / distressed are you about your current sleep disorder? 7. To what extent do you think your sleep disorder is currently interfering with your daytime functioning (e.g., daytime fatigue, mood, ability to do work / daily chores, concentration, memory, mood, etc.)?

[0017] Neither lemborexant nor suvorexant was evaluated for validated clinical endpoints related to daytime dysfunction / daytime sleepiness in patients with insomnia. Furthermore, the ISI generally has a one-month recall period and therefore cannot measure day-to-day fluctuations in daytime dysfunction. Furthermore, only item 7 of the ISI specifically targets daytime function. However, the ISI instrument is not designed to provide meaningful results for a specific subset of items. For example, the post-hoc analysis of lemborexant presented results for items 4–7 of the ISI. Therefore, the ISI may not be a valid instrument for assessing daytime activity / daytime function.

[0018] Insomnia disorder is a chronic condition, and currently available treatments, with the exception of eszopiclone, suvorexant, and lemborexant, are generally limited to short-term use. Caution and dose reductions are often recommended in older adults. Pharmacological treatments aimed solely at sleep-onset insomnia do not provide relief for people with sleep maintenance difficulties, and treatments indicated for people with sleep maintenance insomnia may be associated with a risk of cognitive impairment, postural instability, or next-day residual sedation that may impair driving function [Neubauer Int Rev Psychiatry.2014;26(2):214-24].

[0019] Additionally, use of benzodiazepines and benzodiazepine receptor agonists is associated with an increased risk of falls [McCall Prim Care Companion J Clin Psychiatry.2004;6(1):9-20], leading to hip and femur fractures, increased disability, and healthcare resource utilization. In September 2020, an FDA Drug Safety Communication was issued calling for an update of the Boxed Warning to include the potential for abuse, dependence, and other serious risks to improve the safety of use of the benzodiazepine drug class. https: / / www.fda.gov / drugs / drug-safety-and-availability / fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class) was issued. : "To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring an updated black box warning for all benzodiazepine medications. Benzodiazepines are widely used to treat many illnesses, including anxiety, insomnia, and seizures. Current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medications, which may lead to them being prescribed and used inappropriately. This increases these serious risks, especially when benzodiazepines are used in combination with several other medications and substances.

[0020] Benzodiazepines can be an important therapeutic option for the treatment of disorders for which they are indicated. However, their use, even when taken at recommended doses, can lead to misuse, abuse, and dependence. Abuse and misuse can result in overdose or death, especially when benzodiazepines are used in combination with other medications such as opioid painkillers, alcohol, or illicit drugs. Physical dependence can develop when benzodiazepines are taken consistently for days to weeks, even when taken as prescribed. Stopping them suddenly or rapidly reducing the dose can trigger withdrawal reactions, including seizures. This can cause serious, potentially life-threatening, complications.”

[0021] Generally, insomnia disorders require long-term (chronic) pharmacological treatment that addresses the most prominent and immediate symptoms / clinical pathology of insomnia without negatively impacting next-day functioning. This is a key criterion for defining insomnia according to DSM-5: the sleep disturbance causes clinically significant difficulties or impairments in social, occupational, educational, academic, behavioral, or other important areas of functioning [American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing; 2013].

[0022] Daridrexant was evaluated in a phase 2 clinical trial (NCT02839200; Dauvilliers et al., Ann Neurol 2020;87:347-356; Idorsia media release, June 13, 2019) and was found to cause a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder. Human simulation of daridrexant suggested a high and rapid peak in orexin receptor occupancy and a rapid decline in receptor occupancy at the 25 mg dose. In the phase 2 clinical trial, "visual analog scales (VAS) for morning sleepiness, daytime alertness, and daytime functional ability all showed nonsignificant dose-dependent increases with high-dose daridrexant compared with placebo at week 2, which were not maintained at week 4. This pattern also held true for zolpidem compared with placebo." The authors conclude, "A difference of several hours in half-life can have an important impact on the tendency for a drug to induce a residual next-day effect, highlighted by the absence of such an effect up to the highest dose (i.e., 50 mg) in this study." The authors further state, "One of the major concerns with current insomnia products is the potential for a residual next-day effect. Morning sleepiness assessments showed no differences in next-day sleepiness between any dose of daridorexant and placebo. This is hypothesized to be related to daridorexant's short half-life, as shown in Phase 1 clinical trials in healthy subjects. Daridorexant's relatively short half-life may also result in fewer residual effects. Additionally, daridorexant, like all DORAs, is designed to improve sleep quality, so the lack of a residual next-day effect is not surprising and supports the data showing objective improvement."

[0023] Daridorexant has entered two Phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group, polysomnography studies to evaluate the efficacy and safety of ACT-541468 in adult and elderly subjects with insomnia disorder (NCT03545191, EudraCT Number: 2017-004642-20, testing 25 mg and 50 mg strengths; and NCT03575104, EudraCT Number: 2017-004643-20, testing 10 mg and 25 mg strengths). To assess daytime functioning, the Phase 3 study will use the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) as a validated patient-reported outcome (PRO) instrument, with the IDSIQ sleepiness domain score as a secondary endpoint (S. Hudgens et al., The Patient-Patient-Centered Outcomes Research (2021) 14:249-268). This instrument will be compared with the Daytime Insomnia Symptom Scale (DISS) (Buysse et al., Sleep Medicine 8 (2007) 198-208; Buysse et al., SLEEP 29 (9) (2006) 1155-1165). 73) and is designed to characterize and compare daytime symptoms in insomnia. The IDSIQ consists of three domains (alertness / cognition; (negative) mood; and tiredness / sleepiness) with a total of 14 items, each based on an 11-point numerical rating scale. For the score of each domain, the aggregate rating score of all relevant items is taken into account.

[0024] The Daytime Alertness / Cognition domain score has six items: - How bright did you feel today? 11-point numerical rating scale ranging from "not bright at all" to "very bright"; - How well were you able to concentrate today? 11-point numerical rating scale ranging from "not able to concentrate at all" to "very well able to concentrate"; - How forgetful did you feel today? 11-point numerical rating scale ranging from "not forgetful at all" to "very forgetful"; - How much effort did you put in today to perform your daily activities (i.e., reading, laundry, work, school)? 11-point numerical rating scale ranging from "no effort at all" to "a lot of effort"; - How fresh did you feel today? 11-point numerical rating scale ranging from "not at all fresh" to "very fresh"; - How awake did you feel today? 11-point numerical rating scale ranging from "not at all awake" to "very awake"; The daytime (negative) mood domain score has four items: - How anxious did you feel today? 11-point numerical rating scale ranging from "not at all anxious" to "very anxious"; - How irritable did you feel today because of lack of sleep? 11-point numerical rating scale ranging from "not at all irritable" to "very irritable"; - How angry did you feel today? 11-point numerical rating scale ranging from "not angry at all" to "very angry"; - How stressed did you feel today? 11-point numerical rating scale ranging from "not at all stressed" to "very stressed."

[0025] The daytime sleepiness domain score (which may alternatively be called, for example, the daytime sleepiness / fatigue domain score) has four items: - How energized did you feel today? 11-point numerical rating scale ranging from "not energized at all" to "very energized"; - How mentally fatigued did you feel today? 11-point numerical rating scale ranging from "not mentally fatigued at all" to "very mentally fatigued"; - How physically tired did you feel today? 11-point numerical rating scale ranging from "not at all physically tired" to "very physically tired"; - How sleepy did you feel today? 11-point numerical rating scale ranging from "not sleepy at all" to "very sleepy." Summary of the Invention

[0026] The Phase 3 clinical trial of daridrexant, NCT03545191, now confirms the results of the previous Phase 2 clinical trial, demonstrating that daridrexant significantly improved sleep onset (through a significant reduction in latency to persistent sleep (LPS)) and sleep maintenance (through a significant reduction in wake after sleep onset (WASO)) at the 25 mg and 50 mg doses; and significantly improved subjective total sleep time (sTST) at the 25 mg and 50 mg doses. The phase 3 clinical trial NCT03575104, EudraCT Number: 2017-004643-20, showed that daridrexant 25 mg significantly reduced WASO and increased sTST compared to placebo in months 1 and 3, but not 10 mg, and the reduction in LPS was not statistically significant in this study (significant after logarithmic transformation). Surprisingly, in addition to its nighttime clinical effects (i.e., direct effects on sleep parameters such as sleep onset and / or maintenance, as assessed by WASO, LPS, and / or sTST), daridrexant also improved patients' next-day functioning, particularly as measured using the IDSIQ, particularly the IDSIQ sleepiness domain score, as a secondary clinical endpoint. Daridorexant demonstrated numerical improvements at the low 25 mg dose, while the higher 50 mg dose significantly improved (reduced) the IDSIQ sleepiness domain score versus placebo. In addition, daridorexant improved the IDSIQ mood and wakefulness / cognition domains, as well as the total score, at months 1 and 3. Data indicate that improvements in sleep (WASO, LPS, sTST) were maintained over 3 months and were associated with gradual improvements in daytime functioning over time. [Brief explanation of the drawings]

[0027] [Figure 1] Figure 1: Primary and secondary efficacy endpoints [Figure 2] Figure 1 (continued): Primary and secondary efficacy endpoints [Figure 3] Figure 2: Other IDSIQ endpoints [Figure 4] Figure 2 (continued): Other IDSIQ endpoints DETAILED DESCRIPTION OF THE INVENTION

[0028] Detailed Description of the Invention 1) A first aspect relates to a method for treating sleep disorders (particularly insomnia); the method comprises administering a pharmacologically effective amount of daridorexant or a pharmaceutically acceptable salt thereof to a subject in need thereof; the daridorexant improves the daytime activity of the subject.

[0029] The term "treatment of sleep disorders" is intended to specifically encompass aspects of sleep onset (e.g., as assessed by latency to persistent sleep (LPS)) and / or sleep maintenance (e.g., as assessed by wake after sleep onset (WASO)) and / or subjective total sleep time (sTST).

[0030] Furthermore, such improvement in daytime activity may preferably be assessed by the Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ) patient-reported outcome instrument. In particular, the total IDSIQ score is: - IDSIQ daytime alertness / cognition domain score; - IDSIQ daytime mood domain score; and - IDSIQ daytime sleepiness domain score; is defined as having

[0031] The term "daytime activity" is intended to be synonymous with the term "daytime function," and these terms may be used interchangeably herein.

[0032] The Daytime Alertness / Cognition domain score has six items: - How bright did you feel today? 11-point numerical rating scale ranging from "not bright at all" to "very bright"; - How well were you able to concentrate today? 11-point numerical rating scale ranging from "not able to concentrate at all" to "very well able to concentrate"; - How forgetful did you feel today? 11-point numerical rating scale ranging from "not forgetful at all" to "very forgetful"; - How much effort did you put in today to perform your daily activities (i.e., reading, laundry, work, school)? Did you put in any effort? An 11-point numerical rating scale ranging from "no effort at all" to "a lot of effort"; - How fresh did you feel today? 11-point numerical rating scale ranging from "not at all fresh" to "very fresh"; - How alert did you feel today? 11-point numerical rating scale ranging from "not at all alert" to "very alert."

[0033] The daytime (negative) mood domain score has four items: - How anxious did you feel today? 11-point numerical rating scale ranging from "not at all anxious" to "very anxious"; - How irritable did you feel today because of lack of sleep? 11-point numerical rating scale ranging from "not at all irritable" to "very irritable"; - How angry did you feel today? 11-point numerical rating scale ranging from "not angry at all" to "very angry"; - How stressed did you feel today? 11-point numerical rating scale ranging from "not at all stressed" to "very stressed."

[0034] The daytime sleepiness domain score has four items: - How energized did you feel today? 11-point numerical rating scale ranging from "not energized at all" to "very energized"; - How mentally fatigued did you feel today? 11-point numerical rating scale ranging from "not mentally fatigued at all" to "very mentally fatigued"; - How physically tired did you feel today? 11-point numerical rating scale ranging from "not at all physically tired" to "very physically tired"; - How sleepy did you feel today? 11-point numerical rating scale ranging from "not sleepy at all" to "very sleepy."

[0035] For the avoidance of doubt, any reference herein to the active ingredient daridorexant, in free or pharmaceutically acceptable salt form, is understood to refer interchangeably to daridorexant or a pharmaceutically acceptable salt thereof; such pharmaceutically acceptable salt form of daridorexant is particularly the hydrochloride form.

[0036] 2) Accordingly, a further aspect is that said improvement in said subject's daytime activity is characterized by: - IDSIQ daytime alertness / cognition domain score; and / or - IDSIQ daytime mood domain score; and / or - IDSIQ daytime sleepiness domain score; assessed by at least one of the following; Regarding the method according to embodiment 1); Each of the IDSIQ daytime domain scores, ie, the alertness / cognition domain score, the daytime mood domain score, and the daytime sleepiness domain score (each defined above), form a separate sub-domain.

[0037] In sub-embodiments, particular aspects of the invention relate to such improvements in daytime activity, wherein said daytime activity improves over time, i.e., the magnitude of the effect on daytime activity / daytime function increases over the duration of treatment (e.g., for at least 4 weeks or at least 12 weeks, e.g., especially from week 1 (through week 4) to at least week 12 of treatment); according to embodiment 1) or 2) and according mutatis mutandis to any one of embodiments 3) to 54) described below.

[0038] 3) A further embodiment relates to a method according to embodiment 1), wherein said improvement in said subject's daytime activity is assessed by the IDSIQ daytime sleepiness domain score.

[0039] 4) Another aspect of the present invention relates to a method for treating a sleep disorder (particularly insomnia); the method comprises administering a pharmacologically effective amount of daridorexant or a pharmaceutically acceptable salt thereof to a subject in need thereof; the daridorexant reduces daytime clinical symptoms associated with the sleep disorder (particularly insomnia).

[0040] Such reduction in daytime clinical symptoms may be assessed in particular by the Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ) patient-reported outcome instrument; aspects 2) and 3) shall apply mutatis mutandis.

[0041] 5) A further embodiment relates to a method according to embodiment 4), wherein said daytime clinical symptoms associated with said sleep disorder are symptoms of daytime dysfunction.

[0042] 6) A further embodiment relates to a method according to embodiment 4), wherein said daytime clinical symptoms associated with said sleep disorder are symptoms of daytime sleepiness, in particular symptoms of daytime sleepiness assessed by the IDSIQ daytime sleepiness domain score.

[0043] 7) A further embodiment relates to a method according to any one of embodiments 1) to 6), wherein said improved daytime activity / reduction in daytime clinical symptoms associated with said sleep disorder is exhibited by a subject administered daridorexant, and said subject cumulatively experiences less physical fatigue, less mental fatigue, less sleepiness, and more energy during the day.

[0044] 8) A further embodiment relates to a method according to any one of embodiments 1) to 7), wherein the sleep disorder is a dyssomnia or a sleep disorder associated with a general medical condition.

[0045] 9) A further embodiment relates to a method according to any one of embodiments 1) to 7), wherein the sleep disorder is a sleep disorder.

[0046] 10) A further embodiment relates to a method according to any one of embodiments 1) to 7), wherein the sleep disorder is a sleep disorder associated with a general physical illness.

[0047] 11) A further embodiment relates to a method according to any one of embodiments 1) to 7), wherein the sleep disorder is insomnia associated with a mood disorder (particularly a depressive disorder), insomnia associated with epilepsy, insomnia associated with an autism spectrum disorder, insomnia associated with attention deficit hyperactivity disorder (ADHD), insomnia associated with a neurodegenerative disorder (particularly Alzheimer's disease); insomnia associated with an anxiety disorder, insomnia associated with an addictive disorder or insomnia associated with an appetite disorder.

[0048] 12) A further embodiment relates to a method according to any one of embodiments 1) to 10), wherein the sleep disorder is insomnia.

[0049] 13) A further embodiment relates to a method according to any one of embodiments 1) to 9), wherein the sleep disorder is primary insomnia.

[0050] 14) A further aspect is that said treatment of said sleep disorders (particularly insomnia) has the following therapeutic effect: - Improved sleep onset / reduced latency to persistent sleep (LPS); and / or - Improved sleep maintenance / reduced wake after sleep onset (WASO); and / or - an increase in total sleep time, e.g. total sleep time (sTST) subjectively assessed daily by the patient;

[0033] In relation to the method according to any one of aspects 1) to 13), resulting in at least one, preferably all, of: The effect is particularly to be measured from baseline and compared to placebo; the treatment effect is particularly to be statistically significant.

[0051] 15) A further aspect is that said treatment of said sleep disorders (particularly insomnia) has the following therapeutic effect: - Improved sleep onset / reduced latency to persistent sleep (LPS); and - Improved sleep maintenance / reduced wake-after-sleep-onset (WASO);

[0033] In the method according to any one of aspects 1) to 13), The effect is particularly to be measured from baseline and compared to placebo; the treatment effect is particularly to be statistically significant.

[0052] 16) A further aspect is that said treatment of said sleep disorders (particularly insomnia) has the following therapeutic effect: - improvement in sleep onset / reduction in latency to sleep (LPS); and - Improved sleep maintenance / reduced wake after sleep onset (WASO); and - Increase in total sleep time (sTST) as subjectively assessed by the patient daily;

[0033] In the method according to any one of aspects 1) to 13), The effect is particularly to be measured from baseline and compared to placebo; the treatment effect is particularly to be statistically significant.

[0053] 17) A further embodiment relates to a method according to any one of embodiments 1) to 16), wherein the subject is an adult.

[0054] 18) A further embodiment relates to a method according to any one of embodiments 1) to 16), wherein the subject is an elderly adult (defined as being 65 or older).

[0055] 19) A further embodiment relates to the method according to any one of embodiments 1) to 16), wherein the subject is a pediatric patient (defined as younger than 18). It should be understood that the dose of daridorexant in free or pharmaceutically acceptable salt form (as set out in any one of embodiments 21) to 24) below) may need to be adapted to the pediatric population.

[0056] Any unit dose may need to be adapted to body weight, for example, in a pediatric population. In general, weight measurement may be required for pediatric patients. For daridorexant, weight measurement may be particularly required, for example, for (pediatric) patients weighing less than 40 kg. Such adapted / reduced doses are equivalent to respective doses for an adult patient population (e.g., a unit dose of about 25 mg of daridorexant free base equivalent, or a unit dose of about 50 mg of daridorexant free base equivalent); they must be contained within each adult unit dose.

[0057] 20) A further embodiment relates to a method according to any one of embodiments 1) to 19), wherein the subject has been diagnosed with difficulty falling asleep and / or staying asleep.

[0058] 21) Another aspect of the present invention is a method for administering daridorexant or a pharmaceutically acceptable salt thereof in a unit dose of about 25 mg to about 50 mg of daridorexant; in particular, in a unit dose of about 25 mg of daridorexant or in a unit dose of about 50 mg of daridorexant. The amount of daridorexant in salt form is stated as a free base equivalent), and relates to any one of the methods of embodiments 1) to 20).

[0059] The amount of daridorexant in a given unit dose of daridorexant in embodiment 21) [and similarly in embodiments 22)-24 below] shall be stated as the free base equivalent. When administered in pharmaceutically acceptable salt form, this amount refers to daridorexant in free base form (i.e., the amount of daridorexant stated as the free base equivalent), and the actual amount of such pharmaceutically acceptable salt form of daridorexant (e.g., particularly daridorexant in hydrochloride form) may need to be adjusted accordingly. For example, a unit dose of about 25 mg of daridorexant active ingredient stated as the free base equivalent corresponds to about 27 mg of daridorexant in hydrochloride form; a unit dose of about 50 mg of daridorexant active ingredient stated as the free base equivalent corresponds to about 54 mg of daridorexant in hydrochloride form. Any reference herein to a unit dose is described as the amount of daridrexant active ingredient equivalent to the free base.

[0060] 22) A further embodiment relates to the method of any one of embodiments 1) to 20), wherein daridorexant or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 25 mg of daridorexant or a unit dose of about 50 mg of daridorexant (the amount of daridorexant in salt form is referred to herein as the free base equivalent).

[0061] 23) A further embodiment relates to the method of any one of embodiments 1) to 20), wherein daridorexant or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 25 mg of daridorexant (the amount of daridorexant in salt form is referred to herein as the free base equivalent).

[0062] 24) A further embodiment relates to the method of any one of embodiments 1) to 20), wherein daridorexant or a pharmaceutically acceptable salt thereof is administered in a unit dose of about 50 mg of daridorexant (the amount of daridorexant in salt form shall be stated as the free base equivalent).

[0063] 25) A further embodiment relates to the method of any one of embodiments 1) to 24), wherein daridorexant is in the hydrochloride salt form.

[0064] 26) A further embodiment relates to the method of any one of Embodiments 1) to 24) or Embodiment 25), mutatis mutandis, wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered in the form of a tablet.

[0065] 27) A further embodiment is one in which daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered in the form of a tablet; the tablet - a tablet core, said tablet core comprising at least two, preferably all, of the following excipients: Mannitol, microcrystalline cellulose, povidone, croscarmellose sodium, silicon dioxide and / or magnesium stearate; and a film coat; said film coat comprising at least two, preferably all, of the following excipients: Hypromellose, microcrystalline cellulose, glycerin, talc, titanium dioxide and / or iron oxide; a film-coated tablet having The method relates to any one of aspects 1) to 24) or aspect 25) mutatis mutandis.

[0066] 28) A further embodiment relates to the method of any one of embodiments 1) to 27), wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered once daily.

[0067] 29) A further embodiment relates to the method of any one of embodiments 1) to 28), wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered in the evening.

[0068] 30) A further embodiment relates to the method of any one of embodiments 1) to 28), wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered within 2 hours before bedtime, particularly within 1 hour before bedtime, and more particularly within 30 minutes before bedtime.

[0069] 31) A further embodiment relates to the method of any one of embodiments 1) to 28), wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered within 1 hour before bedtime, particularly within 30 minutes before bedtime. In a subembodiment, the unit dose of daridorexant is administered just before bedtime.

[0070] 32) A further embodiment relates to the method of any one of embodiments 1) to 28), wherein daridorexant (i.e., daridorexant in free or pharmaceutically acceptable salt form, particularly daridorexant in hydrochloride form) is administered between about 0.25 hours and 2 hours (particularly between about 0.25 hours and 1 hour) before bedtime. In a subembodiment, the unit dose of daridorexant is administered immediately before bedtime.

[0071] 33) A further embodiment relates to the method according to any one of embodiments 1) to 32), wherein the subject shows a significant decrease from baseline in sleep maintenance, especially after 1 month and / or 3 months of treatment, especially in sleep maintenance as measured by WASO.

[0072] 34) A further embodiment relates to the method according to any one of embodiments 1) to 32), wherein the subject exhibits a significant decrease from baseline in sleep maintenance, particularly after 3 months of treatment, in particular in sleep maintenance as measured by WASO.

[0073] 35) A further embodiment relates to the method according to any one of embodiments 1) to 34), wherein the subject exhibits a significant decrease from baseline in sleep onset, particularly after 1 month and / or 3 months of treatment, particularly in sleep onset as measured by LPS.

[0074] 36) A further embodiment relates to the method according to any one of embodiments 1) to 34), wherein the subject exhibits a significant decrease from baseline in sleep onset, particularly after 3 months of treatment, particularly in sleep onset as measured by LPS.

[0075] 37) A further embodiment relates to the method according to any one of embodiments 1) to 36), wherein the subject shows a significant increase from baseline in total sleep time, especially after 1 month and / or 3 months of treatment, in particular total sleep time as measured by sTST.

[0076] 38) A further embodiment relates to the method according to any one of embodiments 1) to 36), wherein the subject shows a significant increase from baseline in total sleep time, particularly after 3 months of treatment, in particular total sleep time as measured by sTST.

[0077] 39) A further embodiment relates to a method according to any one of embodiments 1) to 38), wherein the sleep disorder is a chronic sleep disorder.

[0078] 40) A further embodiment relates to the method according to any one of embodiments 1) to 39), wherein the duration of treatment is at least 3 months.

[0079] 41) A further embodiment relates to the method according to any one of embodiments 1) to 39), wherein the duration of treatment is at least 9 months.

[0080] 42) A further embodiment relates to the method according to any one of embodiments 1) to 41), wherein the sleep disorder is caused by or is a result of withdrawal from a benzodiazepine drug or from a non-benzodiazepine benzodiazepine receptor agonist.

[0081] 43) A further embodiment relates to the method according to any one of embodiments 1) to 42), wherein said subject suffers from / has been diagnosed with an anxiety disorder.

[0082] 44) A further embodiment relates to the method according to any one of embodiments 1) to 43), wherein the sleep disorder is insomnia characterized by difficulty falling asleep and / or staying asleep.

[0083] 45) A further embodiment relates to the method according to any one of embodiments 1) to 44), wherein the daridorexant in free or pharmaceutically acceptable salt form is taken no more than once per night, particularly within 30 minutes of going to bed, and especially at least 7 hours before the intended time of waking up.

[0084] 46) Another aspect of the invention relates to a method for treating daytime sleepiness in a subject; the method comprising administering to the subject an effective amount of daridorexant or a pharmaceutically acceptable salt thereof (particularly the hydrochloride form of daridorexant); wherein the subject's daytime sleepiness as assessed by the IDSIQ daytime sleepiness domain score is reduced; particularly wherein the subject has been diagnosed with a sleep disorder.

[0085] 47) A further embodiment relates to the method of embodiment 46), in which one or more of the features of any one of embodiments 7) to 32) are applied mutatis mutandis.

[0086] 48) A further embodiment relates to the method of embodiment 46) or 47), in which one or more of the features of any one of embodiments 33) to 45) are applied mutatis mutandis.

[0087] 49) Another aspect of the present invention relates to a method for treating insomnia and improving sleep and daytime functioning, comprising administering to a subject in need thereof an effective amount of daridorexant in free or pharmaceutically acceptable salt form (particularly daridorexant in hydrochloride form); in particular, the subject's daytime sleepiness as assessed by the IDSIQ daytime sleepiness domain score is reduced.

[0088] 50) A further embodiment relates to the method of embodiment 49), wherein the subject is a patient having difficulty falling asleep and / or maintaining sleep (particularly, the subject is an adult patient).

[0089] 51) A further embodiment relates to the method of embodiment 49) or 50), in which one or more of the features of any one of embodiments 1) to 32) are applied mutatis mutandis.

[0090] 52) A further embodiment is characterized in that one or more of the features of any one of embodiments 33) to 45) The method of embodiment 49) or 50) applies mutatis mutandis.

[0091] 53) A further embodiment relates to daridorexant or a pharmaceutically acceptable salt thereof for use in a method according to any one of embodiments 1) to 32).

[0092] 54) A further embodiment relates to daridorexant or a pharmaceutically acceptable salt thereof for use in a method according to any one of embodiments 33) to 52).

[0093] For the avoidance of doubt, for purposes of the present invention, any amount / unit dose of daridorexant means an amount / unit dose appropriate for administration of daridorexant in the free base form of such amount / unit dose. If daridorexant is present in such a composition in a form other than the anhydrous free base, such as a pharmaceutically acceptable salt, e.g., hydrochloride salt; and / or a solvate form, such as a hydrate, such amount / unit dose may need to be adjusted in the pharmaceutical composition.

[0094] Whenever a dose refers to a specific amount of a unit dose in mg, such unit dose refers to such amount in mg of the active ingredient of daridorexant in free base form, having a molecular weight of 450.93 g / mol. When the active ingredient is administered in the form of a pharmaceutically acceptable salt, such as, for example, the hydrochloride salt, the respective amount of the active pharmaceutical ingredient (e.g., the pharmaceutically acceptable salt) in the pharmaceutical composition should be adjusted accordingly (e.g., 487.39 g / mol for the hydrochloride salt; thus, for example, a unit dose of about 27 mg of daridorexant HCl corresponds to a unit dose of about 25 mg of daridorexant active ingredient; about 54 mg of daridorexant HCl corresponds to a unit dose of about 50 mg of daridorexant active ingredient).

[0095] An effective amount is preferably a pharmacologically effective amount.

[0096] When the plural is used for compounds, solids, pharmaceutical compositions, diseases, etc., it is intended to refer to the singular compound, solid, etc. as well.

[0097] The term "consisting essentially of" is understood in particular in the context of the present invention to mean that the respective composition is present (i.e., in the sense of "consisting of") in an amount of at least 90 weight percent, particularly at least 95 weight percent, especially at least 99 weight percent, and preferably 100 weight percent of the respective composition in the amounts explicitly stated in each embodiment. The term "having" is preferably understood in the sense of the term "consisting essentially of."

[0098] The term "essentially", when used in terms such as "essentially pure", is understood in the context of the present invention to mean that at least 90 weight percent, particularly at least 95 weight percent, and especially at least 99 weight percent of the respective composition / compound etc. is the pure composition / compound / crystalline form etc.

[0099] The term "enantiomerically enriched" is understood, particularly in the context of the present invention, to mean that at least 90 weight percent, preferably at least 95 weight percent, and most preferably at least 99 weight percent of the daridorexant is present in the form of one enantiomer of daridorexant. Daridorexant is understood to exist in the enantiomerically enriched absolute (S)-configuration.

[0100] When not used in reference to temperature, the term "about" before a numerical value "X" is used in this application to mean a range from 10% of XX to X + 10% of X, preferably XX In the specific case of temperatures, the term "about" placed before a temperature "Y" in this application denotes a temperature ranging from Y-10°C to Y+10°C, preferably from Y-5°C to Y+5°C, in particular from Y-3°C to Y+3°C. Room temperature means a temperature of about 25°C. In this application, when the term n equivalents (n is a number) is used, it is intended that within the scope of this application n means about n, preferably n means exactly n.

[0101] Whenever the words "between" or "to" are used to describe a numerical range, it is understood that the endpoints of the stated range are expressly included in that range. This means, for example, that when a temperature range is stated to be between 40°C and 80°C (or 40°C to 80°C), the endpoints 40°C and 80°C are included in the range; or, when a variable is defined as an integer between 1 and 4 (or 1 to 4), it means that the variable is the integer 1, 2, 3, or 4.

[0102] Daridorexant can be used according to the present invention as a medicament, for example in the form of a pharmaceutical composition, especially for enteral or parenteral administration.

[0103] For the avoidance of any doubt, it is understood that any pharmaceutical composition having a pharmaceutically effective amount of daridorexant may further comprise additional conventional excipients and / or additives, which may be used alone or in combination (the quantum satis, i.e., the maximum amount of such additional conventional ingredients and / or additives, may need to be reduced to make the total ww% equal to 100). The total amount expressed as "ww%" of a composition is intended to be 100.

[0104] Reference is made to the extensive literature on the subject of these and other pharmaceutically acceptable excipients and techniques referred to herein, see, e.g., R.C. Rowe, P.J. Seskey, S.C. Owen, Handbook of Pharmaceutical Excipients, 5th ed., Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy, 21st ed. (2005), Part 5, "Pharmaceutical Manufacturing," published by Lippincott Williams & Wilkins.

[0105] The expression "% w / w" (or %(w / w)) means a weight percentage relative to the total weight of the composition under consideration. Unless expressly stated otherwise, the total weight under consideration is the total weight of the pharmaceutical composition.

[0106] The expression (wt / wt) in relation to ratios means the weight ratio of each component.

[0107] When a value is stated as a % value and unless further specified, such value means ww% or, in the case of purity, area% as determined by HPLC.

[0108] Suitable dosage forms for enteral administration may be tablets or capsules (especially tablets) containing a pharmaceutical composition having an effective amount of daridorexant.

[0109] The term "pharmaceutical composition" is interchangeable with the terms "formulation" or "composition."

[0110] The terms "treat" or "treatment" or "treating" when used in reference to a disease means that the disease is cured in a patient or animal; or that the animal or patient is free from the disease. It means that some or all of the symptoms of the disease have been reduced or eliminated, although the person continues to be affected more adversely.

[0111] The terms "subject," and similarly "patient," refer to mammals, particularly humans. In particular, the term "subject" refers to a human patient.

[0112] Sleep disorders include, in particular, sleep disorders associated with sleep abnormalities and general physical illnesses, as well as parasomnias and substance-induced sleep disorders. Sleep abnormalities include, in particular, endogenous sleep disorders (especially insomnia, breathing-related sleep disorders, periodic limb movement disorders, and restless legs syndrome), exogenous sleep disorders, and circadian rhythm sleep disorders. Sleep disorders refer to all types of insomnia, including, in particular, primary insomnia and idiopathic insomnia; intermittent treatment of chronic insomnia; situational transient insomnia (e.g., insomnia associated with a new environment or noise); (short-term) insomnia due to stress, distress, pain, or illness; and insomnia associated with psychiatric or neurological disorders (including insomnia associated with mood disorders (e.g., depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and brain degenerative diseases, including Alzheimer's disease and other neurodegenerative and / or cognitive disorders). In addition, sleep disorders specifically refer to sleep abnormalities such as breathing-related sleep disorders, including (obstructive or central) sleep apnea syndrome; periodic limb movement disorders (nocturnal myoclonus); restless legs syndrome; circadian rhythm sleep disorders, including shift work sleep disorder; and time zone shift (jet lag) syndrome. Sleep disorders also refer to REM sleep disruption. Parasomnias include wakefulness disorders and sleep-wake transition disorders; in particular, parasomnias include nightmare disorders, sleep terror disorders, and sleepwalking. Sleep disorders associated with general physical illnesses are particularly sleep disorders associated with diseases such as psychiatric disorders, neurological disorders, neuropathic pain, and heart and lung diseases. Substance-induced sleep disorders specifically include the subtypes insomnia type, parasomnia type, and mixed type, and particularly include conditions caused by drugs that cause reduced REM sleep as a side effect. Sleep disorders include in particular all types of insomnia as defined above, as well as sleep-related dystonia, restless legs syndrome, sleep apnea, jet lag syndrome, shift work sleep disorder and delayed or advanced sleep phase syndrome. In addition, sleep disorders also include age-related sleep disorders.

[0113] Sleep disorders associated with general physical illnesses include sleep disorders (particularly insomnia) associated with psychiatric or neurological disorders; sleep disorders (particularly insomnia) associated with brain (neuro)degenerative disorders, including mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease and other neurodegenerative and / or cognitive disorders or disorders; and sleep disorders (particularly insomnia) associated with anxiety disorders, addictive disorders, or appetite disorders.

[0114] Mood disorders include major depressive episodes, manic episodes, mixed episodes, and hypomanic episodes; depressive disorders, including major depressive disorder and dysthymic disorder; bipolar disorders, including bipolar disorder type I, bipolar disorder type II (recurrent major depressive episodes with hypomanic episodes), and cyclothymic disorder; mood disorders due to general medical illness (including subtypes with depressive features, with major depressive-like episodes, with manic features, and with mixed features); and mood disorders, including substance-induced mood disorders (including subtypes with depressive features, with manic features, and with mixed features). Such mood disorders are particularly major depressive episodes, major depressive disorder, mood disorders due to general medical illness; and substance-induced mood disorders.

[0115] Anxiety disorders can be distinguished by the primary object or specificity of the fear, ranging from rather vague, as in generalized anxiety disorder, to more specific, as seen in phobic anxiety disorder (PHOB) or post-traumatic stress disorder (PTSD). Thus, anxiety disorders include generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), acute stress disorder, and psychological It may be defined as including post-traumatic stress disorder (PTSD), panic anxiety disorder (PAD) including panic attacks, phobic anxiety (PHOB), simple phobias, social phobia (social anxiety disorder), avoidance disorder, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to general physical illness, and substance-induced anxiety disorders. In a sub-embodiment, a specific example of a limited fear-induced anxiety disorder is phobic anxiety or post-traumatic stress disorder. In particular, anxiety disorders include post-traumatic stress disorder, obsessive-compulsive disorder, panic attacks, phobic anxiety, and avoidance disorder.

[0116] Addiction disorders may be defined as dependence on one or more rewarding stimuli, particularly dependence on one rewarding stimulus. Such rewarding stimuli may be of natural or synthetic origin. Examples of such rewarding stimuli are substances / drugs (natural or synthetic, such as cocaine, amphetamines, opiates (natural or (semi)synthetic, such as morphine or heroin), cannabis, ethanol, mescaline, nicotine, etc.), consumed alone or in combination; or other rewarding stimuli of natural origin (such as food, sweets, fat, or sex) or synthetic origin (such as gambling or the Internet / IT (such as excessive gaming or inappropriate involvement in online social networking sites or blogs)). In a sub-embodiment, addiction disorders related to the use, abuse, seeking, and relapse of psychotropic substances are defined as all types of psychological or physical dependence and their associated tolerance and dependence factors. Substance-related addictive disorders include, in particular, substance use disorders such as substance dependence, substance craving, and substance abuse; substance-induced disorders such as substance addiction, substance withdrawal, and substance-induced delirium. The expression "prevention or treatment of dependence" (i.e., preventive or therapeutic treatment of patients diagnosed as being dependent or at risk of becoming dependent) means reducing dependence, in particular reducing the onset of dependence, attenuating its maintenance, promoting withdrawal, promoting abstinence, or reducing, reducing, or preventing the occurrence of relapse to dependence (in particular reducing the onset of dependence, promoting withdrawal, or attenuating, reducing, or preventing the occurrence of relapse to dependence).

[0117] Appetite disorders include eating disorders and drinking disorders. Eating disorders may be defined to include eating disorders associated with excessive food intake and associated complications; anorexia nervosa; compulsive eating disorders; obesity (regardless of cause, such as genetic or environmental); obesity-related disorders, including overeating and obesity observed in type 2 (non-insulin-dependent) diabetics; bulimia nervosa; cachexia; and binge eating disorders. In particular, eating disorders include metabolic dysfunction; appetite dysregulation; compulsive obesity; bulimia nervosa or anorexia nervosa. In a sub-embodiment, eating disorders may be defined to include, in particular, anorexia nervosa, bulimia nervosa, cachexia, binge eating disorder, or compulsive obesity. Water disorders include polydipsia and all other types of excessive fluid intake in psychiatric disorders. This pathological alteration of eating may result from appetite disorders (food attraction or aversion); altered energy balance (ingestion vs. expenditure); disturbances in perception of food quality (high fat or high carbohydrate, good taste); disturbances in food availability (restricted eating or deprivation) or water balance disorders.

[0118] The term "treatment of sleep disorders" as used herein means in particular the treatment of insomnia; in particular, the treatment of said sleep disorders (in particular insomnia) includes: - Improved sleep onset / reduced latency to persistent sleep (LPS); and / or - Improved sleep maintenance / reduced wake after sleep onset (WASO); and / or - Increase in total sleep time (sTST) as subjectively assessed by the patient daily; brings; The effects are measured from baseline and compared to placebo. Preferably, the treatment produces all of the effects described above in a statistically significant manner. More preferably, the treatment is not significantly associated with any treatment-emergent adverse events (TEAEs), especially not associated with serious TEAEs. (without a TEAE), such TEAEs may include next-morning sleepiness (e.g., assessed each morning by a visual analog scale (VAS)); rebound insomnia, withdrawal symptoms upon cessation of treatment; or suicide, suicidal ideation, or self-harm.

[0119] The term "daytime clinical symptoms" as used herein refers to well-known daytime symptoms of sleep disorders, in particular the daytime clinical symptoms / symptoms of insomnia, especially those identified in DSM-5.

[0120] For the avoidance of any doubt, a method for treating a particular disease or disorder, such as a sleep disorder, as set forth in any one of aspects 1) to 54) herein, comprising administering daridorexant or a pharmaceutically acceptable salt thereof, comprising: - daridrexant or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder according to any one of aspects 1) to 54) of the present specification; - use of daridorexant or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder according to any one of aspects 1) to 54) of the present specification; - daridrexant or a pharmaceutically acceptable salt thereof for use in such a method for treating a disease or disorder as described in any one of aspects 1) to 54) herein; - a medicament for the treatment of a disease or disorder according to any one of aspects 1) to 54) of the present specification; etc. will also be disclosed.

[0121] Similarly, when daridorexant or a pharmaceutically acceptable salt thereof is described as being useful for treating a particular disease or disorder, such as a sleep disorder, as described herein, daridorexant or a pharmaceutically acceptable salt thereof may also be used in combination with other compounds, such as, for example: - for use in the manufacture of a medicament for the treatment of a disease or disorder described herein; - for use in a method for treating a disease or disorder as described herein, the method comprising administering daridorexant or a pharmaceutically acceptable salt thereof; - as a medicament for the treatment of the diseases or disorders described herein; Suitable.

[0122] Certain aspects of the present invention are described in the following examples, which are intended to illustrate the invention in more detail without in any way limiting its scope. [Example]

[0123] Experimental section Abbreviations (used above and below): AE Adverse Event DB double-blind End of Study (EOS) EOT End of treatment IDSIQ Insomnia Daytime Symptoms and Impact Questionnaire h time LPS continuous sleep latency min PSG polysomnography qd (quaque die): once a day (also known as qd) sTST Subjective total sleep time VAS visual analogue scale WASO Awakening Time

[0124] Example 1: The synthesis of daridorexant, [(S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-pyrrolidin-1-yl]-(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone, is described in WO 2013 / 182972 and WO 2015 / 083094. A crystalline salt form of daridorexant is disclosed in WO 2015 / 083071; a crystalline form of daridorexant in free base form is disclosed in WO 2015 / 083070.

[0125] Daridorexant is used in the clinical trial examples below in the form of a stable crystalline hydrochloride salt, which can be prepared as described in WO2015 / 083071 and WO2018 / 202689.

[0126] Film-coated tablets for oral use having strengths of 10 mg, 25 mg and 50 mg of daridorexant HCl (and corresponding placebo tablets) may be manufactured using conventional methods, for example using the following excipients: Tablet core: Mannitol, microcrystalline cellulose, povidone, croscarmellose sodium, silicon dioxide, magnesium stearate.

[0127] Film Coat: Hypromellose, Microcrystalline Cellulose, Glycerin, Talc, Titanium Dioxide, Iron Oxide.

[0128] Example A): A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Polysomnography Study to Evaluate the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects with Insomnia Disorder This study has three phases: screening, treatment, and safety follow-up. The screening phase begins with the signing of an informed consent form at Visit 1 and ends with randomization (Visit 4), provided that subjects meet all eligibility criteria. The screening phase consists of a screening period and a run-in period. The screening period lasts 20–31 days. The screening period begins with Visit 1 and ends with Visit 2. During the screening period, investigators will confirm eligibility criteria and conduct a one-night polysomnography (PSG) assessment in eligible subjects. The screening period will last 7–18 days to allow time for all required procedures at Visit 1, PSG assessment, and collection of a minimum number of eDiary entries (i.e., 7 days) between Visits 1 and 2. The run-in period begins with Visit 2 and ends with randomization (i.e., Visit 4). Eligible subjects at Visit 2 will be assigned to single-blind placebo treatment, which will be administered daily. During the run-in phase, subjects will return to the site for Visit 3, which will consist of two overnight PSGs (PSG nights) and will occur once the subject has completed an electronic diary for at least 7 days and eligibility has been confirmed. The run-in phase will last 13-24 days to allow for the collection of a minimum number of electronic diary entries (i.e., 7 days), the performance of two overnight PSGs at Visit 3, and confirmation of eligibility from the PSG central reader. The double-blind (DB) treatment phase will last 3 months and begin with randomization (Visit 4). DB study treatment will be administered daily. A safety call will be conducted at Visit 5 to collect information on adverse events (AEs) and concomitant medications. Each subject's sleep parameters will be objectively assessed with two consecutive overnight PSGs at Visits 6 and 8. A safety visit without overnight PSGs will be conducted at Visit 7. During this treatment phase, electronic diaries will be completed daily. End-of-Double-Blind-Treatment (EODBT) will occur on the second morning of Visit 8. The safety follow-up phase will begin after EODBT. This will be a 7-day single-blind, placebo-controlled phase. The study consists of a run-out phase and a safety follow-up phase. The run-out phase begins on the evening of Visit 9. Visit 9 consists of one overnight PSG under single-blind placebo treatment. Visit 9 is followed by 6 days of single-blind placebo treatment at home. Electronic diaries are completed daily during the run-out phase. The end of the run-out phase (End-of-Treatment [EOT]) occurs after all visit assessments have been performed at Visit 10. The safety follow-up phase begins after EOT and ends 30 days after the last dose of DB study treatment intake for subjects not enrolled in the ID-078A303 extension study. Subjects who complete DB study treatment and the run-out phase are eligible to enter the ID-078A303 extension study (if approved by national health authorities and the local Independent Ethics Committee / Institutional Review Board). For these subjects, the safety follow-up phase ends on the day of enrollment in ID-078A303. The end of study (EOS) for each subject will be defined as the date of the follow-up phone call on Day 30 (Visit 11) or the date of enrollment in the ID-078A303 Extension Study. If a subject is discontinued from study treatment early, EOS will occur as planned on Day 115. If a subject withdraws consent and no longer wishes to participate in the study, then for that subject, EOS is the date of consent withdrawal. If a subject is declared lost to follow-up, then EOS is the date of the last successful contact with that subject.

[0129] Test treatment Study Treatment: ACT-541468 tablets in 25 mg and 50 mg strengths will be administered orally once daily in the evening during the DB treatment phase.

[0130] Placebo: ACT-541468-matching placebo will be administered orally once daily in the evening during the single-blind run-in period, the DB treatment period, and the single-blind run-out period.

[0131] endpoint Primary Efficacy Endpoint The primary efficacy endpoint of this study is defined as follows: - Change in WASO (sleep maintenance) from baseline to month 1; - Change in WASO from baseline to month 3; - Change in LPS (sleep onset) from baseline to month 1; - Change in LPS from baseline to month 3.

[0132] Baseline is defined as the average of two overnight PSGs at Visit 3. Months 1 and 3 are defined as the average of two overnight PSGs at Visits 6 and 8, respectively.

[0133] LPS (min) is the time from the start of recording to the beginning of the first 20 consecutive epochs (i.e., 10 min) scored as non-wakeful (i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep), or REM as measured by PSG).

[0134] WASO is the time (min) spent awake after the onset of persistent sleep until lights on, as measured by PSG.

[0135] Secondary Efficacy Endpoints The secondary efficacy endpoints of this study are defined as follows: - Change in sTST from baseline to month 1; - Change in sTST from baseline to month 3; - Change in Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ) sleepiness domain score from baseline to month 1; - Change in IDSIQ sleepiness domain score from baseline to Month 3.

[0136] Baseline was the mean value based on home screening sleep diary / IDSIQ completion during the 7 days immediately preceding the first PSG at Visit 3.

[0137] "Month 1" is the mean value based on home sleep diary / IDSIQ completion during the 7 days immediately preceding the first PSG at Visit 6.

[0138] "Month 3" is the mean value based on home sleep diary / IDSIQ completion during the 7 days immediately preceding the first PSG at Visit 8.

[0139] Safety Endpoints: In addition to the standard collection of AEs, safety data specific to insomnia and its treatment will be evaluated as follows: - Withdrawal symptoms (physical dependence) due to discontinuation of treatment will be assessed based on changes in the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) total score (Visits 9 and 10), occurrence of relevant AEs, and significant ECG abnormalities from the last assessment on DB treatment (Visit 8, second morning) to the run-out period.

[0140] - Rebound insomnia will be assessed based on objective sleep parameters (WASO, LPS, and TST) at Visit 9 compared to Visit 3. It will also be assessed using subjective sleep parameters during the run-out phase (subjective WASO [sWASO], subjective sleep onset latency [sLSO], and sTST) compared to baseline.

[0141] - Next-day residual effects from baseline (Visit 3) to Months 1 and 3: -- Coding sub-test (Copyright); --Sheehan Disability Scale (Copyright) (SDS (Copyright)); --Visual analogue scale score (VAS; mm); It is evaluated based on the change in

[0142] - Serious adverse events up to 30 days after discontinuation of DB study treatment or enrollment in the extension study; Treatment-emergent AEs (TEAEs) up to 30 days after discontinuation of DB study treatment or enrollment in the extension study; - AEs leading to early discontinuation of DB study treatment: - AE of special interest (AESI) after determination by the Independent Safety Board (ISB): -- Narcolepsy-like symptoms (i.e., abnormal sleep behavior events, including excessive daytime sleepiness [EDS], cataplexy, and hallucinations / sleep paralysis) -- Suicide / self-harm; - Changes in vital signs (mean systolic and diastolic blood pressure [BP] and pulse rate from two overnight PSGs) from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8); - Change in weight from baseline (Visit 1) to Month 3 (Visit 8); - Significant ECG abnormalities under DB study treatment; - Change in ECG variability from baseline (Visit 3) to Month 3 (Visit 8) and end of run-out (Visit 10); - Significant laboratory abnormalities under DB treatment; - Changes in laboratory variables from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8); - Occurrence of suicidal thoughts and / or behaviors under DB study treatment based on the C-SSRS (copyright).

[0143] statistical methodology Analysis of primary and secondary efficacy endpoints: The probability of a type I error is controlled for testing multiple null hypotheses regarding the two primary endpoints (LPS and WASO) and two other endpoints (sTST and IDSIQ) assessed at 1 and 3 months of treatment and at the two dose levels included in the study, i.e., 25 mg and 50 mg.

[0144] The eight statistical null hypotheses for the primary efficacy endpoint were: Sleep maintenance: H1 WASO : High dose - placebo = 0 for WASO at month 1; H2 WASO High dose-placebo = 0 for WASO at month 3; H3 WASO : Low dose - placebo = 0 for WASO at month 1; H4 WASO : Low dose - placebo = 0 for WASO at month 3; Falling asleep: H1 LPS : High dose - placebo = 0 for LPS at month 1; H2 LPS : High dose - placebo = 0 for LPS at month 3; - H3LPS: low dose-placebo = 0 for LPS at month 1; - H4LPS: low dose-placebo = 0 for LPS at month 3; The eight statistical null hypotheses for the secondary efficacy endpoints were as follows: Amount of sleep: H1 sTST : High dose - placebo = 0 for sTST at month 1; H2 sTST : High dose - placebo = 0 for sTST at month 3; H3 sTST : Low dose - placebo = 0 for sTST at month 1; H4 sTST : Low dose - placebo = 0 for sTST at month 3; Next-day performance: H1 IDSIQ High dose-placebo = 0 for IDSIQ sleepiness domain score at month 1; H2 IDSIQ High dose-placebo = 0 for IDSIQ sleepiness domain score at month 3; H3 IDSIQ Low dose - placebo = 0 for IDSIQ sleepiness domain score at month 1; H4 IDSIQ Low dose - placebo = 0 for IDSIQ sleepiness domain score at month 3; "High dose," "low dose," and "placebo" represent the mean change from baseline for the above endpoints (WASO, LPS, sTST, or IDSIQ sleepiness domain scores) and time points (month 1 or month 3) for the 50 mg, 25 mg, and placebo treatment groups, respectively.

[0145] Each null hypothesis will be tested against the alternative hypothesis, i.e., "ACT-541468 improves WASO / LPS / sTST / IDSIQ sleepiness domain scores compared to placebo at the doses (25 or 50 mg) and time points (month 1 or month 3) listed above."

[0146] Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ) IDSIQ patient-reported outcomes (PRO) instrument (S. Hudgens et al., The Patient The IDSIQ (Patient-Centered Outcomes Research (2021) 14:249-268) is programmed in the subject's language onto an electronic handheld device and must be completed by the subject each evening, without study staff input or intervention, from screening (Visit 1) through EOT (Visit 10), before the evening sleep diary. The IDSIQ consists of three domains (i.e., alertness / cognition; negative mood; fatigue / sleepiness) and has a total of 14 items, each based on an 11-point numeric rating scale. For each domain, the aggregate rating score of all relevant items is considered.

[0147] [Table 1]

[0148] This instrument is based on an existing instrument, the Daytime Insomnia Symptom Scale [Buysse et al., Sleep Med. 2007 Apr;8(3):198-208]. Psychometric validation of the IDSIQ instrument was performed in a phase 2 study (NCT03056053; ID-078A203) conducted in patients with insomnia. The instrument was validated according to FDA guidelines.

[0149] result: The study demonstrated statistically significant effects on all primary and secondary efficacy endpoints, including sTST, for both the 25 mg and 50 mg strengths. Thus, daridrexant improved sleep onset and sleep maintenance by significantly reducing WASO and LPS at both doses; and significantly increased subjective total sleep time (sTST) at both doses.

[0150] For the secondary endpoint, IDSIQ sleepiness domain score, the results are summarized below: The IDSIQ sleepiness domain (items 8, 11, 12, and 13 above) was significantly improved with daridrexant at the 50 mg dose at months 1 and 3, with numerical trends observed at both time points at the 25 mg dose.

[0151] The IDSIQ total score and alertness / cognition and mood domain scores also decreased versus placebo at all time points with both doses of daridorexant. Daridorexant 50 mg improved the IDSIQ mood and alertness / cognition domains (score reductions) and total score at both time points (all P values ​​(uncorrected for multiplicity) for comparisons versus placebo were ≦0.0005).

[0152] Sleep improvements were maintained over 3 months and were associated with progressive improvements in daytime functioning over time.

[0153] Daridorexant was well tolerated and had a favorable safety profile in both adult and elderly patients. Adverse event rates were comparable between placebo and daridorexant at both treatment doses. The absence of next-morning somnolence is consistent with the pharmacokinetic profile of daridorexant. The incidence of somnolence was low (lower with daridorexant 50 mg versus placebo) and not dose-dependent. The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis and headache. The number of serious adverse events was higher in the placebo group compared with the daridorexant treatment group. There was no next-morning somnolence effect assessed each morning by visual analog scale (VAS). There was no rebound insomnia or withdrawal symptoms upon discontinuation, and no suicide, suicidal ideation, or self-harm was observed. In the study in Example A), there were fewer falls in the 50 mg dose group compared with placebo.

[0154] Figure 1 (Figure 1 and Figure 1 cont.): Primary and secondary efficacy endpoints: Figure 1 shows the least squares mean change from baseline to months 1 and 3 in WASO (Panels A and B), LPS (Panels C and D), sTST (Panels E and F), and IDSIQ sleepiness domain score (Panels G and H) in Study 1 (Example A; left side) and Study 2 (Example B; right side). WASO and LPS data are averages of two consecutive nights of polysomnography recordings during the 3-month double-blind treatment period. sTST and IDSIQ sleepiness domain score data are based on averages of daily recordings over the 7 days prior to overnight polysomnography. Error bars represent the 95% confidence interval. Two-sided P values ​​shown are versus placebo and are statistically significant under type I error control.

[0155] Figure 2 (Figure 2 and Figure 2 cont.): Other IDSIQ endpoints: Figure 1 shows the least squares mean change in scores from baseline to months 1 and 3 in the Insomnia Daytime Symptoms and Impact Questionnaire (IDSIQ) arousal / cognition domain (Panels A and B), mood domain (Panels C and D), and total score (Panels E and F) in Study 1 (Example A; left) and Study 2 (Example B; right). IDSIQ scores are based on the average of daily entries over the 7 days prior to overnight polysomnography. Error bars represent 95% confidence intervals.

[0156] Example B): A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Polysomnography Study to Evaluate the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects with Insomnia Disorder This study (NCT03575104) will be conducted similarly to the study in Example A) using 10 mg and 25 mg strengths of daridorexant.

[0157] result: Please refer to FIG. 1 (FIG. 1 and continuation of FIG. 1) and FIG. 2 (FIG. 2 and continuation of FIG. 2).

[0158] Daridorexant 25 mg significantly reduced WASO and increased sTST compared with placebo at months 1 and 3, but this was not seen at 10 mg, and the reduction in LPS was not statistically significant. After logarithmic transformation, daridorexant 25 mg significantly reduced LPS at months 1 and 3. Numerical trends were observed at both time points for the drowsiness domain of the IDSIQ with the 25 mg dose.

[0159] Example C): ID-078A301 and ID-078A302 to Evaluate the Long-Term Safety and Tolerability of ACT-541468 in Adult and Elderly Subjects with Insomnia Disorder A multicenter, double-blind, parallel-group, randomized, placebo-controlled, three-dose, 40-week extension study This study (NCT03679884) is an extension of the studies in Examples A) and B) and may provide longer-term data, particularly data at 3 months that confirm the effects observed in Examples A) and / or B).

Claims

1. Daridrexant: 【Chemistry 1】 in free or pharmaceutically acceptable salt form, A therapeutic agent for sleep disorders that improves daytime activity in a subject to which it is administered, The improvement in daytime activity is characterized by: - IDSIQ daytime sleepiness domain score; Evaluated by the therapeutic agent comprising daridorexant in free or pharmaceutically acceptable salt form is administered in a pharmaceutical unit dosage form suitable for oral administration of 25 mg±10% daridorexant or in a pharmaceutical unit dosage form suitable for oral administration of 50 mg±10% daridorexant; A therapeutic drug with a treatment period of 3 months.

2. Daridrexant: 【Chemistry 2】 in free or pharmaceutically acceptable salt form, 1. A therapeutic agent for reducing daytime clinical symptoms associated with a sleep disorder, comprising: the daytime clinical symptoms associated with sleep disturbance are symptoms of daytime sleepiness as assessed by the IDSIQ daytime sleepiness domain score; the therapeutic agent comprising daridorexant in free or pharmaceutically acceptable salt form is administered in a pharmaceutical unit dosage form suitable for oral administration of 25 mg±10% daridorexant or in a pharmaceutical unit dosage form suitable for oral administration of 50 mg±10% daridorexant; A therapeutic drug with a treatment period of 3 months.

3. The therapeutic agent described in claim 1 or 2, wherein the improvement in daytime activity / reduction in daytime clinical symptoms associated with the sleep disorder is expressed by a subject administered daridrexant, and the subject gradually experiences less physical fatigue, less mental fatigue, less sleepiness, and more energy during the day.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the sleep disorder is a sleep disorder or a sleep disorder associated with a general physical disease.

5. The therapeutic agent according to any one of claims 1 to 3, wherein the sleep disorder is insomnia.

6. The treatment of insomnia has the following therapeutic effects: - reduction of latency to persistent sleep (LPS); and / or - reduction of wake-onset time (WASO); and / or - an increase in total sleep time (sTST) subjectively assessed by the patient daily; The therapeutic agent according to claim 5, which produces at least one of the following effects:

7. The therapeutic agent according to claim 6, which is used for a subject diagnosed with difficulty falling asleep and / or maintaining sleep.

8. The therapeutic agent according to any one of claims 1 to 3, wherein the therapeutic agent containing daridorexant in the form of a free or pharmaceutically acceptable salt is administered in a pharmaceutical unit dosage form suitable for oral administration of 50 mg ± 10% of daridorexant.

9. The treatment of insomnia has the following therapeutic effect: - Reduction in latency to persistent sleep (LPS); - reduction in wake-onset time (WASO); and - an increase in total sleep time (sTST) subjectively assessed by the patient daily; brings about 6. The therapeutic agent of claim 5, wherein the therapeutic agent containing daridorexant in free or pharmaceutically acceptable salt form is administered in a pharmaceutical unit dosage form suitable for oral administration of 50 mg±10% of daridorexant.

10. Improved daytime activity / reduced daytime clinical symptoms associated with said sleep disorder; a decrease in the latency to persistent sleep (LPS); A reduction in the wake after onset time (WASO); and an increase in total sleep time (sTST) as subjectively assessed by the patient daily; is statistically significant in a clinical endpoint measured at 3 months of treatment.

11. The therapeutic agent of claim 8, wherein daridrexant is in the hydrochloride salt form.

12. the therapeutic agent is in tablet form; The tablet is A tablet core, said tablet core comprising at least two of the following excipients: Mannitol, microcrystalline cellulose, povidone, croscarmellose sodium, silicon dioxide and / or magnesium stearate; and a film coat; said film coat comprising at least two of the following excipients: Hypromellose, microcrystalline cellulose, glycerin, talc, titanium dioxide and / or iron oxide; A film-coated tablet having The therapeutic agent according to claim 11.

13. The therapeutic agent of claim 6 , wherein the therapeutic agent is administered within 1 hour before bedtime.

14. The therapeutic agent according to claim 6, wherein the sleep disorder is chronic insomnia.

15. A therapeutic agent for the treatment of insomnia, which improves sleep and daytime function, comprising daridorexant in free or pharmaceutically acceptable salt form, and which significantly reduces daytime sleepiness as assessed by the IDSIQ daytime sleepiness domain score; the therapeutic agent comprising daridorexant in free or pharmaceutically acceptable salt form is administered in a pharmaceutical unit dosage form suitable for oral administration of 50 mg±10% of daridorexant; A therapeutic drug with a treatment period of 3 months.

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