TREATMENT OF DISORDERS WITH TASIMELTEON

Abstract

Tasimelteon improves sleep in individuals experiencing an advance in established bedtime.

Claims

1. A method of treating an individual experiencing a sleep-wake-cycle-disrupting advance in the individual's established bedtime comprising administering to the individual an amount of tasimelteon effective to reduce one or more untoward consequences of the resulting disruption of said individual's established sleep-wake cycle.

2. The method of claim 1, wherein the advance in the individual's established bedtime is eight hours and caused by eastward jet aircraft travel.

3. The method of claim 2, wherein the amount of tasimelteon administered is 20 mg per day, administered for at least three consecutive days prior to bedtime, in an immediate release form, with the first dose administered prior to the first bedtime following the sleep-wake-cycle disrupting advance.

4. The method of claim 3, wherein the reduction of untoward consequences is an improvement in at least one sleep parameter selected from a group consisting of: total sleep time, latency to persistent sleep, and wake after sleep onset.

5. The method of claim 4, wherein the improved sleep parameter is total sleep time.

6. The method of claim 5, wherein total sleep time is improved in the first two-thirds of the night on the third night following tasimelteon administration.

7. The method of claim 3, wherein the reduction of untoward consequences is an improvement in next day alertness.

8. The method of claim 7, wherein the improvement in next day alertness includes an improvement on the Karolinska Sleepiness Scale, an improvement on the Visual Analog Scale, or both.

9. The method of claim 2, wherein the advance in the individual's established bedtime is six to eight hours and the amount of tasimelteon administered is 20 mg per day, administered in an immediate release form for three consecutive days prior to bedtime, with the first dose administered prior to the first bedtime following the sleep-wake-cycle disruption.

10. (canceled)

11. The method of claim 1, wherein the individual experiences the sleep-wake-cycle disrupting advance as a result of eastbound jet aircraft travel.

12. The method of claim 11, wherein the individual experiences a significantly improved total sleep time during the first two-thirds of the night, during the night following the administration of the third dose of tasimelteon, in both subjective and objective measures of sleep.

13. (canceled)

14. (canceled)

15. The method of claim 1, wherein the sleep-wake-cycle-disrupting advance occurs upon arrival, following an eastbound jet aircraft flight, in which clock time is advanced at the destination of up to eight hours relative to the clock time at the origin of the flight.

16-18. (canceled)

19. The method of claim 1, wherein the individual experiences an increase in total REM sleep, a reduction in the time to accumulation of 30 minutes of REM sleep, or both.

20. A method of treating jet lag in an individual subjected to eastward travel from a place of origin through six to eight time zones to a place of destination during overnight travel by air, said method comprising orally administering to the individual 20 mg tasimelteon in an immediate release form following arrival at the place of destination at or prior to the individual's bedtime in the place of destination.

21. The method of claim 20, wherein prior to the individual's bedtime in the place of destination means between 30 minutes and two hours prior to said individual's bedtime corresponding to the clock time of the individual's regular bedtime at his place of origin.

22. The method of claim 20, wherein prior to the individual's bedtime in the place of destination means within one and one-half hours of such bedtime.

23. (canceled)

24. (canceled)

25. The method of claim 20, wherein the individual is an individual who is pre-selected based on having suffered jet lag disorder as a result of previous similar travel experience.

26. The method of claim 20, wherein the individual is administered tasimelteon once daily for at least three days.

27-29. (canceled)

30. A pre-packaged dispensing unit comprising: (a) a number of individual tasimelteon unit doses each containing 20 mg of immediate release tasimelteon sufficient to provide a course of treatment for an individual to be treated for a jet lag disorder; and (b) a pharmaceutically acceptable container for said unit doses.

31. A dispensing unit of claim 30 in which the number of unit doses therein is 3, 4, or 5 and the container therefor is a blister pack containing one 20 mg tasimelteon tablet per blister.

Description

EXAMPLES

[0026] Aspects of the invention are more fully understood based from the clinical trial results described in Examples 1 and 2, as set out below.

Example 1

[0027] A Phase III clinical study of 318 healthy volunteers demonstrates the efficacy of tasimelteon in treating jet lag disorder. In the course of the trial, volunteers are subjected to a circadian challenge of an 8-hour advance in their usual bedtime, consistent with the circadian challenge induced in travelers crossing eight time zones (e.g., Los Angeles to London or Washington, D.C. to Moscow) and typically causing jet lag disorder.

[0028] The results of this study demonstrate highly significant and clinically meaningful effects of a 20 mg dose of tasimelteon on the primary endpoint of the study, as well as multiple secondary endpoints. The pre-specified primary endpoint used for this purpose is the amount of sleep time in the first two thirds of the night. Secondary endpoints include measures of various sleep parameters—total sleep time (TST), latency to persistent sleep (LPS), and wake after sleep onset (WASO)—as well as next day alertness, measured using the Karolinska Sleepiness Scale (KSS) and Visual Analog Scale (VAS). Table 1 below provides a summary of the primary and secondary endpoint results.

TABLE-US-00001 TABLE 1 p-value p-value Assessment Endpoint Hetlioz ® Placebo Diff Summary Detail PSG TST.sub.2/3* 216.4 156.1 60.31 P < 0.001 3.29E−12 (minutes) TST.sub.full 315.8 230.3 85.46 P < 0.001 3.74E−14 LPS 21.8 36.8 −15.08 P < 0.01  8.08E−03 WASO 144.6 219.1 −74.58 P < 0.001 3.41E−12 KSS (1-9) average 4.0 4.5 −0.53 P < 0.01  8.28E−03 VAS (0-100) average 60.8 54.2 6.59 P < 0.01  9.89E−03 *primary endpoint

[0029] These results demonstrate the effectiveness of tasimelteon in treating jet lag disorder. The magnitude of the total sleep time benefit of 85 minutes' improvement over placebo is highly clinically meaningful. The measurements of next day alertness on both the KSS and VAS scales are also meaningful and underscore the ability of tasimelteon to address both nighttime and daytime symptoms of jet lag disorder.

[0030] Tasimelteon was also shown to significantly increase the total rapid eye movement (REM) sleep period while also significantly decreasing the time required to accumulate 30 minutes of REM sleep. These results are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Assess- p-value ment Endpoint Hetlioz ® Placebo Difference Summary PSG REM.sub.Total 48.9 35.2 13.7 <0.0001 (min.) (min.) REM.sub.Accumulate 318.7 372 −53.3 <0.0001 (%) REM.sub.Achieved 76.1 51.6 24.5 <0.001

[0031] Thus, tasimelteon demonstrated significant improvement in the accumulation of REM sleep, which is strongly regulated by the circadian pacemaker, during an 8-hour phase advance in sleep timing. These results suggest that tasimelteon increases sleep during circadian adverse timing at least in party by affecting the circadian pacemaker and further support tasimelteon as a novel circadian regulator for the treatment of JLD.

Example 2

[0032] A two-phase transatlantic travel study of 25 subjects (tasimelteon n=13, placebo n=12) comprises a first phase that is an observational travel study to collect baseline data, and a second phase that is a treatment phase. Participants in the study travel either five or eight time zones from Washington, D.C. to London (five time zones) or San Francisco or Los Angeles to London (eight time zones). Participants stay at their destination for three nights and four days and during randomization receive 20 mg of tasimelteon for three consecutive nights prior to their bedtime. Efficacy is monitored by PSG as well as sleep and wake questionnaire scales.

[0033] During the baseline phase, sleep is most disturbed in the third night, as shown in Table 3 below.

TABLE-US-00003 TABLE 3 Baseline TST.sub.2/3 (minutes) Night 1 Night 2 Night 3 217.8 (59.78) 249.8 (51.62) 197.5 (88.76)

[0034] The primary endpoint of the study is TST for the first ⅔ of the night(s) most likely to be disrupted. These are, from Table 2, Night 3, followed by Night 1 and Night 2.

[0035] Table 4 below reports the effect of tasimelteon versus placebo on TST.sub.2/3 and TST.sub.full on Night 3, as well as measures of sleep quality, sleep latency, and WASO.

TABLE-US-00004 TABLE 4 Change from baseline Endpoint HETLIOZ ® Placebo Difference p-value Objective TST.sub.2/3 Night 3 76.2 41.4 34.8 p = 0.0354 TST.sub.2/3 All 3 nights 131.4 40.9 90.6 p = 0.0785 Subjective TST.sub.Full Night 3 111.9 33.5 78.5 p = 0.0225 TST.sub.Full All 3 Nights 240.0 65.1 174.9 p = 0.0423 Sleep Quality Night 3 1.31 0.36 0.95 p = 0.0198 Sleep Latency Night 3 −20.6 6.0 −26.5 p = 0.0347 WASO Night 3 −81.1 −24.7 −56.4 p = 0.0840 Global PGI-S Day 3 −0.71 −0.07 −0.63 p = 0.0168 measures KSS Day 4 −1.69 −0.69 −1.00 p = 0.0765

[0036] As can be seen in Table 4, tasimelteon significantly improves both objective and subjective measures of sleep. Tasimelteon-treated patients sleep 76 minutes longer during the first ⅔ of Night 3 and a total of 131 minutes longer during the first ⅔ of all three nights during their treated travel as compared to their baseline observational travel.

[0037] Subjective measures of TST, sleep quality, sleep latency, and WASO made using a Post-Sleep Questionnaire (PSQ) demonstrate a similar improvement among tasimelteon-treated participants. Measures of global function, including Patient Global Impression of Severity (PGI-S) and KSS also favor tasimelteon.

[0038] 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. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0039] The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present disclosure is presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the disclosure. Any embodiments chosen and described herein appear in order to best explain the principles of the disclosure and the practical application, and to enable others of ordinary skill in the art to understand the disclosure for various embodiments with various modifications as are suited to the particular use contemplated.