Methods for improving sleep

Abstract

The present invention provides a method for improving sleep in a patient having a variant of the cryptochrome circadian clock 1 (CRY1) genotype associated with delayed sleep-wake phase disorder (DSWPD) of circadian rhythm sleep disorder (CRSD).

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of co - pending U.S. Provisional Patent Application Serial No. 62 / 805,057, filed on February 13, 2019, which is hereby incorporated herein by reference in its entirety. Background of the Invention

[0003] Circadian Rhythm and Sleep

[0004] The timing of human sleep is controlled by two regulatory processes. The first - sleep homeostasis, which maintains a balance between wake time (during which fatigue accumulates) and sleep time (which is restorative and prepares the individual for the next awakening). The second - an endogenous rhythm regulated by the circadian pacemaker in the suprachiasmatic nucleus (SCN), which counteracts the effects of fatigue with signals emanating from the circadian pacemaker. At night, when the homeostatic drive for sleep is high, signals promoting wakefulness peak. Then, as the individual approaches bedtime, the output of the SCN weakens and sleep ensues.

[0005] Sleep - wake disorders can be caused by a misalignment between an individual's circadian pacemaker and his / her scheduled sleep times. Such disorders are classified as circadian rhythm sleep disorders (CRSD) and include various subtypes, including shift work sleep disorder (SWSD), delayed sleep - wake phase disorder (DSWPD), jet lag, and non - 24 - hour sleep - wake disorder (Non - 24).

[0006] Several circadian clock genes have been identified. These include cryptochrome circadian clock 1 (CRY1), cryptochrome circadian clock 2 (CRY2), period 1 (PER1), period 2 (PER2), and period 3 (PER3) genes. Variations in these genes can lead to differences in circadian rhythm and sleep / wake cycle phenotypes.

[0007] For example, mutations in the CRY1 gene are associated with Delayed Sleep-Wake Phase Disorder (DSWPD), a form of insomnia in which sleep onset and offset are shifted to later times. DSWPD is the most common diagnostic type in CRSD, estimated to occur in 0.2%–10% of the general population. Currently, the pathophysiology of DSWPD remains unclear, and suspected causes include different sensitivities of an individual's circadian clock to environmental entrainment cues such as the light / dark cycle and alterations in the oscillator properties that affect its period length. A specific CRY1 allele, rs184039278, has been associated with familial DSPD. This gain-of-function CRY1 variant results in reduced expression of key transcriptional targets and an extended period of the circadian molecular rhythm, providing a mechanistic link to DSWPD symptoms. In animal studies, expression of this protein results in an increase in the circadian rhythm of approximately half an hour.

[0008] Melatonin

[0009] Melatonin has a distinct circadian rhythm pattern. In healthy individuals with nocturnal sleep, circulating melatonin concentrations are low during waking days, increase significantly about 1 to 3 hours before bedtime, remain high throughout sleep, and decrease near waking. Onset, offset, and midpoint are commonly used to mark the phases of the endogenous melatonin rhythm. Measurement of circadian rhythm phases, such as the Dim Light Melatonin Onset (DLMO), improves the diagnosis and treatment of sleep-wake disorders. The DLMO can be measured to collect a reliable, non-invasive marker of circadian phase. In patients with DSWPD, consistent with phase delay, the entrained DLMO occurs significantly later, far later than expected in normal chronotype subjects.

[0010] Tasimelteon

[0011] Tasimelteon is a circadian rhythm regulator that acts as a melatonin receptor agonist with selective activity for melatonin receptor type 1 (MT1) and type 2 (MT2). Tasimelteon has been approved by the US Food and Drug Administration for the treatment of Non-24 Circadian Sleep-Wake Disorder in people over 18 years of age and by the European Medicines Agency specifically for people who are totally blind.

[0012] Clinical studies have demonstrated the following efficacy of tasimelteon: phase shifting the circadian timing system (CTS) and improving nocturnal sleep and reducing daytime sleep, as well as accelerating the circadian clock synchronization in totally blind patients with Non-24. Summary of the Invention

[0013] In a first aspect, the present invention provides a method for treating a patient with circadian rhythm sleep disorder (CRSD), the method mainly comprising administering to the patient an amount of tasimelteon effective to treat the disorder, the improvement comprising: selecting a patient for said treatment by identifying that the patient has a cryptochrome circadian clock 1 (CRY1) genotype associated with said disorder.

[0014] In another aspect, the present invention provides a method for treating a patient exhibiting one or more symptoms of circadian rhythm sleep disorder, the method comprising: identifying that the patient has a cryptochrome circadian clock 1 (CRY1) genotype associated with said disorder, and administering to the patient an amount of tasimelteon effective to treat the disorder.

[0015] In yet another aspect, the present invention provides a method for improving one or more sleep parameters of an individual, the method comprising: identifying that the individual has a variant of the cryptochrome circadian clock 1 (CRY1) genotype associated with circadian rhythm sleep disorder (CRSD); and administering to the individual an amount of tasimelteon effective to improve one or more sleep parameters of the individual daily at a time close to the individual's established bedtime.

[0016] In yet another aspect, the present invention provides a method for treating a patient with circadian rhythm sleep disorder (CRSD), the method mainly comprising administering to the patient an amount of tasimelteon effective to treat the disorder, the improvement comprising: selecting a patient for said treatment by identifying that the patient has a period 1 (PER1) genotype associated with said disorder.

[0017] In another aspect, the present invention provides a method for treating a patient exhibiting one or more symptoms of circadian rhythm sleep disorder, which comprises: identifying that the patient has a period 1 (PER1) genotype associated with said disorder, and administering to the patient an amount of tasimelteon effective to treat the disorder.

[0018] In yet another aspect, the present invention provides a method for improving one or more sleep parameters of an individual, the method comprising: identifying that the individual has a variant of the period 1 (PER1) genotype associated with circadian rhythm sleep disorder (CRSD); and administering to the individual an amount of tasimelteon effective to improve one or more sleep parameters of the individual daily at a time close to the individual's established bedtime. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1Shows total sleep time (TST) data for two groups of individuals treated with tasimelteon according to the present invention. The two groups of individuals are: wild-type (WT) individuals without the rs184039278 cryptochrome circadian clock 1 (CRY1) allele and mutant (MT) individuals with at least one copy of the rs184039278 CRY1 allele.

[0020] Figure 2 Shows the TST during the last third of the night for WT individuals (0 / 0) without the rs112474322 PER1 allele and MT individuals with a copy of the rs112474322 allele. Detailed Description

[0021] In a study of genetic variations related to the sleep-wake pattern, the applicant found a significant association between the rs184039278 CRY1 allele and the therapeutic efficacy of tasimelteon. Specifically, after administering tasimelteon before bedtime, individuals with at least one copy of the rs184039278 CRY1 allele showed improvement in one or more sleep parameters selected from the group consisting of: latency to persistent sleep (LPS); sleep efficiency (%) during the first, second, and / or last third of the night; rapid eye movement (REM) sleep duration; total sleep time (TST), including during the first two-thirds of the night; and wake after sleep onset (WASO).

[0022] Table 1 below shows the TST and sleep efficiency data for two individuals diagnosed with DSWPD and having at least one copy of the rs184039278 CRY1 allele, who were administered 20 mg of tasimelteon before bedtime. It can be seen that these individuals showed higher TST and sleep efficiency.

[0023] Table 1

[0024]

[0025] Figure 1 Shows the TST data for individuals with at least one copy of the rs184039278 CRY1 allele (MT) compared to individuals without at least one copy of the rs184039278 CRY1 allele (WT). Both groups were administered 20 mg of tasimelteon before bedtime. It can be seen that the TST of WT individuals was not only lower but also more variable compared to MT individuals.

[0026] As described above, the rs184039278 CRY1 allele is associated with familial DSWPD. What is not known and cannot be predicted from the literature is the association between the rs184039278 CRY1 allele and the efficacy of tasimelteon in the general treatment of sleep disorders or specifically in the treatment of DSWPD.

[0027] Other variants of the CRY1 and PER1 genes have also been found to be associated with DSWPD. These include the rare rs780614131 allele, which results in the deletion of exon 6.

[0028] For example, Table 2 below shows the observed sleep times of three individuals identified as heterozygous for the rs780614131 allele. It can be seen that the sleep cycle of each individual is delayed compared to what is considered a normal or typical sleep cycle.

[0029] Table 2

[0030] Age Sleep cycle Individual 1, male 33 2:30+30’–11:00 Individual 2, male 57 3:00+20’–11:00 Individual 3, female 28 3:30+10’–13:00

[0031] Similarly, individuals heterozygous for the rs112474322 allele exhibit a later-shifted sleep during the last third of the night compared to individuals without the rs112474322 allele. These results are shown in Figure 2 .

[0032] Aspects of the present invention are applicable to treating any individual having a loss-of-function (LOF) genotype. A LOF genotype is a genotype in which the function of a gene (e.g., CRY1 and / or PER1) associated with CRSD is reduced or lost compared to the wild-type or non-LOF genotype. Those skilled in the art will recognize that a genotype that results in a complete loss of gene function is a LOF genotype. Those skilled in the art will also recognize that a genotype that results in a reduced gene function (where the reduction in gene function is clinically or phenotypically measurable) compared to the wild-type genotype will also constitute a LOF genotype.

[0033] While the invention has been described in connection with the specific embodiments outlined above, it is apparent that many alternatives, modifications, and variations will be apparent to or are intended to be embraced by those skilled in the art. Accordingly, the embodiments of the invention set forth above are intended to be illustrative and not limiting. Various changes may be made without departing from the spirit and scope of the invention as defined in the appended claims. All patents, patent applications, scientific articles, and other published documents cited herein are incorporated herein by reference in their entirety for the substance of their disclosure.

Claims

1. Use of tasimelteon in the preparation of a medicament for treating delayed sleep-wake phase disorder (DSWPD) in a patient having a cryptochrome circadian clock 1 (CRY1) genotype associated with said disorder, wherein said genotype is a CRY1 genotype associated with said disorder having at least one copy of the rs184039278 allele.

2. The use according to claim 1, wherein the CRY1 genotype associated with said disorder is a loss-of-function (LOF) genotype.

3. The use according to claim 1, wherein tasimelteon is administered to the patient once daily before bedtime.

4. The use according to claim 3, wherein tasimelteon is administered at a dose of 20 mg.

5. Use of tasimelteon in the preparation of a medicament for improving one or more sleep parameters in an individual having a variant of the cryptochrome circadian clock 1 (CRY1) genotype and suffering from delayed sleep-wake phase disorder (DSWPD), wherein said genotype is a CRY1 genotype having the rs184039278 allele.

6. The use according to claim 5, wherein the variant of the CRY1 genotype is a loss-of-function (LOF) genotype.

7. The use according to claim 5, wherein tasimelteon is administered to the individual once daily before bedtime.

8. The use according to claim 7, wherein the amount of tasimelteon is 20 mg.

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