Tasimelteon for use in the treatment of patients with optic nerve hypoplasia in order to improve sleep parameters

Abstract

The invention provides methods of improving sleep in a patient having optic nerve hypoplasia (ONH). In one aspect, the invention provides a method of treating a patient having optic nerve hypoplasia (ONH), the method comprising: administering to said patient a dose of tasimelteon effective to improve at least one sleep parameter of the patient.

Description

[0001] TASIMELTEON FOR USE IN THE TREATMENT OF PATIENTS WITH OPTIC NERVE HYPOPLASIA IN ORDER TO IMPROVE SLEEP PARAMETERS

[0002] Cross-Reference to Related Applications

[0003] This application claims priority to co-pending US Provisional Patent Application Serial No. 63 / 501,174, filed 10 May 2023, which is hereby incorporated herein as though fully set forth.

[0004] Background

[0005] Circadian Rhythm and Sleep

[0006] The timing of human sleep is governed by two regulatory processes. The first — the sleep homeostat — preserves the balance between waking hours, during which fatigue accumulates, and sleeping hours, which are restorative and prepare an individual for the next episode of wakefulness. The second — an endogenous rhythm regulated by the circadian pacemaker in the suprachiasm atic nucleus (SCN) — counteracts the effects of fatigue with signals emanating from the circadian pacemaker. In the evening, when the homeostatic drive for sleep is high, wakefulness-promoting signals peak. Then, as an individual approaches bedtime, output from the SCN subsides and sleep ensues.

[0007] Sleep-wake disturbances may result from a misalignment of the individual’s circadian pacemaker and his / her scheduled sleep time. Such a disturbance is classified as a circadian rhythm sleep disorder (CRSD) and includes various sub-types, including shift work sleep disorder (SWSD), delayed sleep-wake phase disorder (DSWPD), jet lag, and non-24-hour sleep-wake disorder (Non-24).

[0008] Delayed Sleep-Wake Phase Disorder

[0009] DSWPD is a common CRSD that typically emerges in a patient’s teens. It is characterized by delayed sleep as compared to the normal light-dark cycle, resulting in difficulty initiating sleep at a desired or appropriate time and, as a consequence, in waking at a desired or appropriate time. When not constrained to a typical light-dark cycle, sleep quality may be normal but delayed from a normal diurnal schedule, while sleep duration may be normal or prolonged. There is currently no approved treatment for DSWPD. Optic Nerve Hypoplasia

[0010] Optic Nerve Hypoplasia (ONH) is a congenital disorder affecting the optic disc and can result in moderate to sever vision loss as a consequence of underdevelopment of the optic nerve. ONH may occur unilaterally or bilaterally and may be associated with abnormal white- or grey-matter development as well as hydrocephalus, and corpus callosum abnormalities. Neurologic abnormalities are more common in patients with bilateral ONH.

[0011] Melatonin

[0012] Melatonin has a distinct circadian pattern. In a healthy nocturnal-sleeping individual, circulating melatonin concentration is low during the waking day, shows a distinct rise about one to three hours before bedtime, remains high throughout sleep, and decreases close to wake-up time. The onset, offset, and midpoint are often used to mark the phase of the endogenous melatonin rhythm. Measurement of circadian phase such as the dim light melatonin onset (DLMO) improves diagnosis and treatment of sleep wake disorders. DLMO may be measured to collect a reliable, non- invasive, circadian phase marker. In DSWPD patients, consistent with a phase delay, entrained DLMO occurs significantly later, well after the time expected in a subject of normal chronotype.

[0013] Tasimelteon

[0014] Tasimelteon is a circadian regulator that acts as a melatonin receptor agonist with selective activity at Melatonin, Type 1 (MTi) and Type 2 (MT2), receptors. Tasimelteon (HETLIOZ®) has received market authorization for the treatment of the CRSD Non-24-Hour Sleep-Wake Disorder (Non-24) in people over 18 years of age by the Food and Drug Administration and specifically in the totally blind from the European Medicines Agency. Tasimelteon is the first and only medicine approved for the treatment of a CRSD.

[0015] Clinical studies have demonstrated the efficacy of tasimelteon to phase advance the circadian timing system (CTS) and to improve nighttime sleep and decrease daytime sleep, as well as to speed the synchronization of the body clock in totally blind patients with Non-24. Summary

[0016] In a first aspect, the invention provides a method of treating a patient having optic nerve hypoplasia (ONH), the method comprising: administering to said patient a dose of tasimelteon effective to improve at least one sleep parameter of the patient.

[0017] In a second aspect, the invention provides, in a method of administering tasimelteon to a patient suffering from delayed sleep-wake phase disorder (DSWPD), an improvement comprising: selecting as the patient an individual suffering from optic nerve hypoplasia (ONH).

[0018] Detailed Description

[0019] During a double-blind, randomized clinical study to evaluate the effects of tasimelteon versus placebo in delayed sleep-wake phase disorder (DSWPD) patients, an 11-month open-label extension (OLE) phase is included. During the OLE phase, patients answer daily sleep diaries and are instructed to take one 20 mg dose of tasimelteon 60 minutes before their desired bedtime. Desired bedtime is defined as the time the patient would need to go to bed the night before a commitment in order to feel fully rested in the morning.

[0020] During the initial placebo run-in and treatment phases, a 24-year-old female patient is identified who is diagnosed with DSWPD and optic nerve hypoplasia (ONH), with confirmed delayed dim light melatonin onset (DLMO). The patient reports an inability to fall asleep at their desired bedtime for longer than three months as well as the ability to have a full night’s sleep when not required to be up at a specific time. This patient participates in the placebo run-in and treatment phases as well as the OLE phase.

[0021] Before the study, the ONH patient reports taking 5 mg of melatonin on Sunday through Thursday nights with a bedtime of 23:30 and sleep onset between 00:30 and 02:00. On Friday and Saturday nights, when melatonin is not taken, sleep onset is between 01:00 and 02:00, with a wake time of approximately noon.

[0022] The patient’s pre-study Momingness-Eveningness Questionnaire (MEQ) total score is 24, indicating a clear eveningness preference. Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires result in a sleep disturbance score of 62 and a sleep-related impairment score of 59.

[0023] DLMO is determined to occur at 23:14, significantly later than in control subjects. As used herein, delayed DLMO is defined as DLMO occurring after or within 30 minutes before a desired bedtime and after 21:30. DLMO is calculated and defined as the clock time when the melatonin concentration of a subject exceeds the mean of three low consecutive values, plus twice the standard deviation of these points.

[0024] Between the blinded placebo run-in phase and the OLE phase, the ONH patient experiences a 72-minute improvement in sleep onset. Average sleep onset is 01:27 AM during screening, 1:54 AM during placebo run-in, and 00:42 AM during the OLE phase.

[0025] During the OLE, the patient went to bed at 00:00 and woke between 07:30 and 09:00 and substantially maintained this schedule on both weekdays and on weekends. Following completion of the OLE and the cessation of treatment, the patient’s sleep time shifted to 01:00 to 02:00.

[0026] At screening, the patient reports symptoms as moderate (3) on the Patient Global Impression of Severity (PGI-S) and as mild (2) during the OLE phase. The patient reports symptoms as much improved (2) on the Patient Global Impression of Change (PGI-C). An investigator similarly reports the patient’s symptoms as much improved (2) on the Clinical Global Impression of Change (CGI-C) during the OLE phase.

[0027] The patient experienced no significant changes in physical examinations, vital signs, ECGs, suicidal ideations or behaviors, or BML Clinical laboratory assessments (hematology, chemistry, urinalysis) were consistent throughout the study.

[0028] The patient is also determined to carry two variants in the Atonal BHLH Transcription Factor 7 (ATOH7) gene known to be associated with ONH — rs61854782 and rs7916697.

[0029] Compared to the blinded placebo run-in phase, tasimelteon demonstrates an ability to shift sleep onset to an earlier time in patients with DSWPD as well as improve symptoms using the PGI-S, PGI-C, and CGI-C scales. In addition, these results suggest potential treatments for patients with ONH or sighted patients with Non-24.

[0030] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0031] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any related or incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a patient having optic nerve hypoplasia (ONH), the method comprising: administering to said patient a dose of tasimelteon effective to improve at least one sleep parameter of the patient.

2. The method of claim 1, wherein the patient suffers from delayed dim light melatonin onset (DLMO).

3. The method of claim 1, wherein the patient suffers from delayed sleep-wake phase disorder (DSWPD).

4. The method of claim 1, wherein the at least one sleep parameter is selected from a group consisting of: time to sleep onset and total sleep time.

5. The method of claim 1, wherein improvement in the at least one sleep parameter is measured as an improvement in at least one scale selected from a group consisting of: PGI-S, PGI-C, and CGI-C.

6. The method of claim 1, wherein administering includes administering the dose of tasimelteon before a desired bedtime of the patient.

7. The method of claim 6, wherein administering includes administering the dose of tasimelteon about 60 minutes before the desired bedtime.

8. The method of claim 1, wherein the dose of tasimelteon is between about 10 mg and about 100 mg.

9. The method of claim 8, wherein the dose of tasimelteon is between about 20 mg and about 50 mg.

10. The method of claim 9, wherein the dose of tasimelteon is about 20 mg.

11. The method of claim 1, wherein the dose of tasimelteon is administered orally.

12. In a method of administering tasimelteon to a patient suffering from delayed sleep-wake phase disorder (DSWPD), the improvement comprising: selecting as the patient an individual suffering from optic nerve hypoplasia (ONH).

13. The improvement of claim 12, wherein the patient suffers from delayed dim light melatonin onset (DLMO).

14. The improvement of claim 12, wherein administering tasimelteon includes administering tasimelteon at a dose effective to improve at least one sleep parameter of the patient selected from a group consisting of: time to sleep onset and total sleep time.

15. The improvement of claim 14, wherein improvement in the at least one sleep parameter is measured as an improvement in at least one scale selected from a group consisting of: PGI-S, PGI-C, and CGI-C.

16. The improvement of claim 12, wherein administering tasimelteon includes administering tasimelteon before a desired bedtime of the patient.

17. The improvement of claim 16, wherein administering tasimelteon includes administering tasimelteon about 60 minutes before the desired bedtime.

18. The improvement of claim 12, wherein administering tasimelteon includes administering between about 10 mg and about 100 mg of tasimelteon.

19. The improvement of claim 18, wherein administering tasimelteon includes administering between about 20 mg and about 50 mg of tasimelteon.

20. The improvement of claim 19, wherein administering tasimelteon includes administering about 20 mg of tasimelteon.

21. The improvement of claim 12, wherein administering tasimelteon includes administering tasimelteon orally.

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