NZ729901B2 - Tasimelteon for treating smith-magenis syndrome - Google Patents

Abstract

Embodiments of the invention relate to the treatment of sleep disturbances with daily administration of melatonin receptor agonist Tasimelteon, in individuals with Smith-Magenis Syndrome (SMS).

Description

TASIMELTEON FOR TREATING SMITH-MAGENIS SYNDROME CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US provisional application number 62/044,856, filed 2 September 2014, and co-pending US provisional application number 62/ 169,635, filed 2 June 2015, each of which is hereby incorporated herein as though fully set forth.

BACKGROUND Smith-Magenis Syndrome (SMS) is a rare (1 in 25,000 births) clinically- recognizable syndrome resulting from an interstitial deletion of 17p11.2 or a mutation of the RAM gene.

SMS is characterized by a distinct pattern of minor craniofacial and skeletal anomalies, expressive speech/language , psychomotor and growth retardation, and a striking neurobehavioral phenotype. This phenotype includes stereotypies, self- injurious and aggressive behaviors.

A common m of SMS is a chronically disrupted sleep pattern, which is found at all ages. Severe sleep disturbances are lly universal in SMS patients (75%-100% individuals/caregivers report symptoms), thus representing a major challenge to the patient and family. Sleep disturbances continue across the lifespan; infants typically present with hypersomnolence. Early in life, however, extreme sleep disturbances, including difficulty g asleep, inability to enter or maintain REM (rapid eye movement) sleep, reduced night sleep, shortened and broken sleep cycles with frequent time and early g awakenings and excessive daytime sleepiness, begin in early toddlerhood and last into adulthood. Furthermore, disturbed sleep appears to be the strongest predictor of maladaptive behavior in children with SMS, including temper tantrums, hyperactivity, attention s, and “sleep attacks.” One of the likely contributing factors to these sleep disturbances is an apparent “inverse” circadian pattern of the hormone melatonin which is normally released only at night whereas its tion is inhibited by light. Several studies have reported that plasma melatonin in SMS patients is high during the day and low at night, which is opposite of the normal pattern. Whether this apparent “inverted” nin secretion pattern is constant within the same individual and sal across SMS patients is still uncertain, as the underlying cause for this disrupted daytime melatonin secretory pattern is unknown. However, findings ed of two patients, whose melatonin secretory n and light induced inhibition were normal, are significant because they t that the sleep disturbances in SMS may not be solely uted to the abnormal diurnal melatonin secretion.

Significant progress has been made in the tanding of the genetic basis of the SMS syndrome. However, the molecular basis of the circadian rhythm tion and of other c features of the phenotype have not been fully characterized and a WO 36619 2015/047610 greater understanding of the cellular and molecular control of both the circadian clock and pineal functioning will provide options for pharmacological interventions that could address the most severe symptoms of the disease. Until a e understanding of the ical anomaly present in SMS is obtained, treatment with conventional drugs, like beta-blockers and exogenous melatonin (in the US), will not actorily improve nt sleep patterns and behavior in SMS patients and ore will not consistently ease the burden on patients and their families. At the t time, there is no effective treatment for sleep bances in SMS.

SUMMARY OF THE INVENTION In one embodiment, the invention provides a method for the treatment of sleep bances in a patient with SMS that comprises internally administering to the patient an effective amount of tasimelteon daily.

In another embodiment, the invention provides a method of treating a sleep disorder in an individual suffering from SMS, the method comprising: inhibiting melatonin production in the individual during waking hours; and administering to the individual an effective amount of a melatonin agonist prior to sleep.

In another embodiment, the invention provides a method of regulating melatonin production in an individual exhibiting light-induced melatonin production, the method comprising: ting melatonin production in the individual during waking hours; and stimulating nin production in the individual during sleep.

In still another embodiment, the invention provides a method of treating a sleep disorder in an individual suffering from SMS, the method comprising: inhibiting melatonin production in the individual during waking hours; and stimulating melatonin production in the individual during sleep.

BRIEF PTION OF THE DRAWINGS These and other features of this invention will be more readily understood from the following detailed description of the various aspects of the invention taken in conjunction with the accompanying drawings that depict various embodiments of the invention, in which: FIGS. 1—3 show measured cortisol levels and light exposure levels for an individual with SMS during three consecutive days of a study; and FIGS. 4—6 show measured melatonin levels and light exposure levels for an individual with SMS during three consecutive days of a study.

It is noted that the drawings of the invention are not to scale. The drawings are intended to depict only typical aspects of the invention, and therefore should not be considered as limiting the scope of the ion.

DETAILED DESCRIPTION Applicants have carried out a study with the objectives to characterize the circadian rhythms of individuals with SMS as measured by plasma melatonin and cortisol, evaluate if there is an association between the melatonin or cortisol circadian patterns (delayed, advanced, Non-24, variable) and various aspects of the SMS phenotype (ex: ng patterns, behavioral problems), determine if there is an ation between the characteristics of the genetic mutation (e.g., extent of the l7pll .2 deletion, RAIl on) and the levels and circadian patterns of melatonin and cortisol and/or the response to a melatonin suppression test (MST), and assess light sensitivity in individuals with SMS as determined by a Melatonin Suppression Test (MST).

This study consisted of three phases: a screening phase followed by an evaluation phase with an optional variable phase for subjects whose circadian melatonin profile warrants further igation.

During the screening phase, ipants were provided t/assent and initial eligibility was evaluated. Subjects were asked to provide information regarding their prior SMS diagnosis, to complete all baseline oral ments and quality of life questionnaires, and allow a blood sample to be obtained for genetic testing.

Samples were sent to a core genetic laboratory for a ed analysis of the RAM gene. Results of the analysis did not need to be returned before subject began the trial if the diagnosis meet eligibility criteria.

During the evaluation phase, three testing segments (TS l and TS3) were , TS2, conducted one week apart at weeks 1, 2, and 4, respectively. These segments ed 36-hour melatonin and cortisol ments where blood samples were taken every hour from an indwelling catheter. When the subject arrived for TSl, they were fitted with an aphy watch to assess light exposure and monitor activity. Blood samples were begun on the first night at 20:00 hours and continued hourly for 36 hours during each g period.

The variable phase consisted of an optional melatonin suppression test (MST) for individuals determined to have a delayed, advanced, or Non-24 circadian profile.

During the MST, plasma samples were collected every hour for the measurement of melatonin. One to two hours after melatonin onset, subjects were d to bright light for 180 minutes, with the exposure timed to coincide with the expected peak in plasma melatonin concentrations. During the period of light exposure, blood samples were collected every 30 minutes.

Results Eight participants, aged 7 to 35, with history of severe sleep disturbances and a cytogenetic confirmed SMS diagnosis completed the evaluation phase. The timing of the melatonin and cortisol ases was consistent during the 4 week assessment, with a circadian period of ~ 24.0 hours. Melatonin secretion occurred mainly during the e hours with a mean acrophase between approximately 2:00 pm and 5:30 pm and very low levels or no melatonin produced during the nighttime, except for one participant for whom the melatonin secretion ase occurred around 5:00 am. The mean cortisol ase ranged from about 9:00 am to 11:30 am in all participants. The sleep/wake pattern recorded by actigraphy showed a severely nted nighttime sleep period with le bouts of activity, and daytime naps or periods of no or little activity. These patterns were variable between ipants and n days.

Individuals with SMS showed an abnormal daytime, but stable, secretion pattern of plasma melatonin believed to be responsible for the severe sleep disorder. In contrast, their cortisol rhythm appears to be normal. Individuals with SMS suffer from severe nighttime sleep disturbances characterized in particular by multiple periods of nighttime activity that frequently interrupt the sleep period, resulting in poor sleep efficiency, variable sleep onset and morning awakenings, and unpredictable sleep quality.

The sleep disorder, which is believed to be the strongest predictor of maladaptive behavior in SMS individuals, including sive behavior, temper tantrums, hyperactivity, attention deficits, constitutes a major challenge to the patients and their families. Its detailed characterization is essential in developing an ive treatment, which is crucially needed.

Tasimelteon Tasimelteon is a ian regulator which binds specifically to two high affinity melatonin receptors, Mella (MTlR) and Mellb (MTZR). These receptors are found in high density in the suprachiasmatic s of the brain (SCN), which is responsible for synchronizing our sleep/wake cycle. Tasimelteon has been shown to improve sleep parameters in prior clinical studies, which simulated a desynchronization of the circadian clock. Tasimelteon has so far been studied in hundreds of individuals and has shown a good bility profile.

Tasimelteon has the chemical name: trans-N-[[2-(2,3-dihydrobenzofuran yl)cycloprop-lyl]methyl]propanamide, has the structure of Formula I.

Formula I lteon is disclosed in US Patent No. 5,856,529 and in US Patent Application Publication No. 2009/0105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78 °C (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater y for MT2R relative to MTlR. Its affinity (K) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. lteon is useful in the practice of this invention because it is a nin agonist.

In d aspects, this invention relates to the use of a tasimelteon metabolite as the melatonin agonist. Tasimelteon metabolites include, for example, a phenol- carboxylic acid analog (M9) and a hydroxypropyl-phenol analog (M11). Each is formed in humans following oral stration of lteon.

Specifically, aspects of the invention encompass use of tasimelteon or of compounds of Formulas II or III, including salts, solvates, and hydrates of tasimelteon or of compounds of Formula II or Formula III, in amorphous or crystalline form.

Formula II (M11) Formula III (M9) While depicted herein in the R-trans configuration, the invention nevertheless comprises use of isomers thereof, i.e., R-cis, S-trans, and S-cis. In addition, the invention comprises use of prodrugs of tasimelteon or of compounds of Formula II or of Formula III, including, for example, esters of such compounds. The discussion that follows will refer to tasimelteon but it is to be understood that the nds of a II and III are also useful in the practice of aspects of the invention.

Metabolites of tasimelteon include, for example, those described in “Preclinical Pharmacokinetics and Metabolism of EMS-214778, a Novel Melatonin Receptor Agonist” by Vachharajani et al., J. Pharmaceutical Sci., 92(4):760-772, which is hereby orated herein by reference. The active metabolites of tasimelteon can also be used in the method of this invention, as can pharmaceutically acceptable salts of tasimelteon or of its active metabolites. For e, in addition to metabolites of Formula II and 111, above, lites of tasimelteon also include the monohydroxylated analogs M13 of Formula IV, M12 of Formula V, and M14 of Formula VI.

Formula IV Formula V Formula VI Tasimelteon can be synthesized by procedures known in the art. The preparation of a 4-vinyl-2,3-dihydrobenzofuran cyclopropyl intermediate can be carried out as described in US Patent No. 7,754,902, which is incorporated herein by reference as though fully set forth.

Pro-drugs, e.g., esters, and pharmaceutically acceptable salts can be prepared by exercise of routine skill in the art.

Treatment ofSMS-related sleep disturbances In at least some individuals with SMS, melatonin production increases with light exposure—light—induced melatonin production— a pattern opposite that expected. For example, FIGS. 4—6 show nin secretion (thick line) and a patient’s light exposure (thin line) during days 1, 2, and 3 of the study. A strong correlation is seen between light exposure and melatonin production. FIGS. 1—3 show similar results for a patient’s cortisol secretion (thick line).

The disrupted sleep patterns of SMS patients—or other individuals exhibiting light-induced melatonin production—may be treated by inhibiting melatonin production during waking hours and/or increasing melatonin production during sleep.

For example, melatonin production may be inhibited by reducing exposure of the individual’s eyes to light using, for example, light blocking or light filtering eyewear.

Such eyewear may include sses, contact lenses, etc., as will be apparent to one skilled in the art. Light filtering eyewear may be operable to filter a broad spectrum of light or, for example, a wavelength or range of wavelengths ined to stimulate melatonin production.

In other embodiments of the invention, melatonin production may be inhibited by stering to the dual an effective amount of a beta blocker. In some embodiments of the invention, such stration may be made using a device operable to deliver to the individual a dosage of a beta r in tion to the dual’s exposure to light as measured, for example, using a light sensor, light meter, or similar tus in communication with or incorporated into the device. sing melatonin production may include administering a melatonin agonist to the individual. In some embodiments of the invention, the melatonin agonist may be tasimelteon and may be administered at a dosage of between about 5 mg and 100 mg, e.g., n about 20 mg and about 50 mg, e.g., about 20 mg once daily prior to sleep, e.g., between about 0.5 hours and about 1.5 hours prior to sleep, e.g., about 1 hour prior to sleep.

Improvements in sleep bances may be measured in any number of ways, including, for example, improvement in nighttime sleep, which may include a reduction in the percentage of wake period within the t’s sleep interval; improvement in one or more of the following: total amount of nighttime sleep; number, timing, and length of nighttime awakenings; sleep onset; wake time; number, timing, and length of daytime naps; improvement in clinical global impression of change (CGI-C); improvement in al global impression of ty (CGI-S); and improvement in behavior.

In the case of treatment with tasimelteon administration, treatment effects may be ined by ongoing daily administration of tasimelteon. Tasimelteon administration may, according to some embodiments of the invention, be ed with the inhibition of nin activity in the patient during waking hours by, for example, one or more of: reducing the exposure of the patient’s eyes to light, internally administering to the patient an active pharmaceutical ingredient that inhibits melatonin production, or internally administering to the patient an active pharmaceutical ingredient that antagonizes melatonin activity Other aspects and embodiments of the invention will be apparent to one skilled in the art from the description above and the appended summary of the study and are Within the scope of the invention.

Claims (10)

1. Use of tasimelteon in the manufacture of a medicament for the treatment of sleep disturbances in a patient with Smith-Magenis Syndrome, wherein treatment comprises the internal administration to the patient of an effective amount of the medicament once daily before bedtime.

2. The use of claim 1, wherein the treatment of sleep disturbance is manifested as an improvement in ime sleep.

3. The use of claim 2, wherein the improvement in nighttime sleep is manifested as a reduction in the percentage of wake period within the patient's sleep interval.

4. The use of claim 1, wherein the treatment of sleep disturbances is manifested as improvement in one or more of the following: total amount of nighttime sleep; number, timing, and length of nighttime awakenings; sleep onset; wake time; number, , and length of daytime naps; improvement in clinical global impression of change ); improvement in clinical global impression of severity (CGI-S); and improvement in or.

5. The use of claim 1, wherein the dose of tasimelteon is n about 5 mg/day and about 100 mg/day.

6. The use of claim 5, wherein the dose of tasimelteon is about 20 mg/d.

7. The use of claim 1, wherein the tasimelteon is formulated for administration n one-half hour and two hours before bed time.

8. The use of claim 7, wherein the lteon is formulated for administration between one-half hour and one and one-half hours before bed time.

9. The use of claim 8, wherein the lteon is formulated for administration one hour before bed time.

10. The use of claim 1, wherein the treatment effects are maintained by ongoing daily administration of tasimelteon.