NZ765911B2 - Tasimelteon for treating smith-magenis syndrome - Google Patents

Abstract

Embodiments of the invention relate to the treatment of sleep disturbances in individuals with Smith-Magenis Syndrome (SMS).

Description

TASIMELTEON FOR TREATING SMITH-MAGENIS SYNDROME CROSS-REFERENCE TO RELATED ATIONS This application claims the bene?t of US provisional application number 62/044,856, ?led 2 ber 2014, and co-pending US provisional application number 62/ 169,635, ?led 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) ally- izable syndrome resulting from an interstitial deletion of 17p11.2 or a on of the RAM gene.

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

A common symptom of SMS is a chronically disrupted sleep pattern, which is found at all ages. Severe sleep disturbances are virtually universal in SMS patients (75%-100% individuals/caregivers report ms), thus representing a major challenge to the patient and family. Sleep disturbances continue across the lifespan; infants typically present with hypersomnolence. Early in life, r, extreme sleep disturbances, including dif?culty falling asleep, inability to enter or maintain REM (rapid eye movement) sleep, reduced night sleep, shortened and broken sleep cycles with frequent night-time and early morning awakenings and excessive e 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 de?cits, 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 production 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 te of the normal pattern. Whether this apparent "inverted" melatonin ion pattern is constant within the same individual and universal across SMS patients is still uncertain, as the underlying cause for this disrupted daytime melatonin secretory pattern is unknown. However, ?ndings reported of two patients, whose nin ory pattern and light induced inhibition were normal, are signi?cant because they suggest that the sleep disturbances in SMS may not be solely uted to the al diurnal melatonin secretion. cant progress has been made in the understanding of the genetic basis of the SMS syndrome. However, the molecular basis of the circadian rhythm disruption and of other speci?c features of the phenotype have not been fully characterized and a 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 precise understanding of the ical y present in SMS is obtained, treatment with conventional drugs, like lockers and exogenous melatonin (in the US), will not satisfactorily improve aberrant sleep patterns and or in SMS patients and therefore will not consistently ease the burden on patients and their families. At the present time, there is no effective treatment for sleep disturbances in SMS.

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

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

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

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

BRIEF DESCRIPTION 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 ed nin 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 gs are intended to depict only typical aspects of the invention, and therefore should not be considered as limiting the scope of the invention.

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 ian patterns (delayed, advanced, , variable) and various aspects of the SMS phenotype (ex: sleeping patterns, behavioral problems), determine if there is an association between the characteristics of the genetic mutation (e.g., extent of the l7pll .2 deletion, RAIl mutation) and the levels and circadian patterns of melatonin and cortisol and/or the response to a melatonin ssion 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 pro?le warrants further investigation.

During the screening phase, participants were provided consent/assent and initial eligibility was evaluated. Subjects were asked to provide information ing their prior SMS diagnosis, to complete all baseline behavioral assessments 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 detailed analysis of the RAM gene. Results of the analysis did not need to be returned before subject began the trial if the diagnosis meet ility 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 included 36-hour melatonin and ol assessments where blood samples were taken every hour from an indwelling catheter. When the subject arrived for TSl, they were ?tted with an actigraphy watch to assess light exposure and monitor activity. Blood samples were begun on the ?rst 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 d, advanced, or Non-24 circadian pro?le.

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

Results Eight participants, aged 7 to 35, with history of severe sleep disturbances and a cytogenetic ed SMS diagnosis completed the evaluation phase. The timing of the nin and cortisol acrophases was consistent during the 4 week assessment, with a circadian period of ~ 24.0 hours. Melatonin secretion occurred mainly during the daytime 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 acrophase occurred around 5:00 am. The mean cortisol acrophase ranged from about 9:00 am to 11:30 am in all participants. The wake pattern recorded by actigraphy showed a severely fragmented nighttime sleep period with multiple bouts of activity, and e naps or periods of no or little ty. These patterns were variable between participants and between days.

Individuals with SMS showed an abnormal daytime, but , secretion pattern of plasma melatonin believed to be sible for the severe sleep disorder. In contrast, their ol rhythm appears to be normal. Individuals with SMS suffer from severe nighttime sleep disturbances characterized in particular by multiple periods of nighttime activity that ntly interrupt the sleep period, resulting in poor sleep ef?ciency, 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 aggressive or, temper tantrums, hyperactivity, attention de?cits, constitutes a major challenge to the patients and their families. Its detailed characterization is essential in ping an effective treatment, which is crucially .

Tasimelteon Tasimelteon is a circadian regulator which binds speci?cally to two high af?nity melatonin receptors, Mella (MTlR) and Mellb (MTZR). These receptors are found in high density in the suprachiasmatic nucleus of the brain (SCN), which is responsible for synchronizing our wake cycle. Tasimelteon has been shown to improve sleep parameters in prior clinical studies, which simulated a desynchronization of the ian clock. Tasimelteon has so far been studied in hundreds of duals and has shown a good tolerability pro?le.

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

Formula I Tasimelteon 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% l, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a ted solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times r af?nity for MT2R relative to MTlR. Its af?nity (K) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a nin agonist.

In related 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 administration of tasimelteon.

Speci?cally, aspects of the invention encompass use of tasimelteon or of nds 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 ration, the invention nevertheless comprises use of stereoisomers 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 tood that the compounds of Formula II and III are also useful in the practice of aspects of the invention.

Metabolites of tasimelteon include, for e, 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 incorporated 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, metabolites of tasimelteon also include the monohydroxylated analogs M13 of Formula IV, M12 of Formula V, and M14 of a VI.

Formula IV 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 bed 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 re—light—induced melatonin production— a pattern opposite that expected. For example, FIGS. 4—6 show melatonin secretion (thick line) and a t’s light exposure (thin line) during days 1, 2, and 3 of the study. A strong correlation is seen between light exposure and melatonin tion. 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 dual’s eyes to light using, for example, light blocking or light ?ltering eyewear.

Such eyewear may include eyeglasses, contact lenses, etc., as will be apparent to one skilled in the art. Light ?ltering eyewear may be operable to ?lter a broad spectrum of light or, for example, a wavelength or range of wavelengths determined to stimulate melatonin production.

In other embodiments of the invention, nin production may be inhibited by stering to the individual an effective amount of a beta blocker. In some embodiments of the invention, such administration may be made using a device operable to deliver to the individual a dosage of a beta blocker in proportion to the individual’s exposure to light as measured, for example, using a light sensor, light meter, or similar apparatus in communication with or incorporated into the device.

Increasing melatonin tion may include administering a melatonin agonist to the individual. In some embodiments of the invention, the nin agonist may be tasimelteon and may be administered at a dosage of between about 5 mg and 100 mg, e.g., between about 20 mg and about 50 mg, e.g., about 20 mg once daily prior to sleep, e.g., n about 0.5 hours and about 1.5 hours prior to sleep, e.g., about 1 hour prior to sleep.

Improvements in sleep disturbances may be measured in any number of ways, including, for example, improvement in ime sleep, which may include a reduction in the percentage of wake period within the patient’s sleep interval; improvement in one or more of the ing: total amount of nighttime sleep; , timing, and length of ime awakenings; sleep onset; wake time; number, timing, and length of e naps; improvement in clinical global impression of change (CGI-C); improvement in clinical global impression of severity (CGI-S); and improvement in behavior.

In the case of treatment with tasimelteon administration, treatment effects may be maintained by ongoing daily administration of tasimelteon. Tasimelteon stration may, according to some embodiments of the ion, be combined 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 t an active pharmaceutical ingredient that antagonizes melatonin ty 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 (6)

1. Use of tasimelteon in the manufacture of a medicament for the treatment of ptive behavior in a patient with Smith-Magenis Syndrome (SMS), wherein treatment ses 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 medicament includes a dose of tasimelteon between about 5 mg/day and about 100 mg/day.

3. The use of claim 2, wherein the dose of tasimelteon is about 20 mg/d.

4. The use of any one of the preceding , wherein the medicament is formulated for stration between one-half hour and two hours before bed time.

5. The use of any one of the preceding claims, wherein the tasimelteon is formulated for administration between one-half hour and one-and-one-half hours before bed time.

6. The use of any one of the preceding claims, wherein the tasimelteon is formulated for administration one hour before bed time. Cortisol 196 182 168 154 140 126 112 98 84 70 56 42 28 14 00:00 all/0,. 00 ”Ix/”zap 00: n,n..”lunnuuuumuu ///////ll/////.I.11.151611114101411 l””////////////////////////////////// 66 ”?ay/”,1,”' ”’"u ll/I/I/I/I/I/I/I/I/I/If/Illfl/I/l/I/Il/I 'IIII’I"III"7,2712%gzzzzggzzgg 7’0/ll/ll/Iz //////// l 4 (””0”) ”., 00: ///I u” ”u,””,””..... 00 .’.’.”///7/}',;;,}';,',',',',,,,,,.. . ..,,,,,u,,,,,,,,,,,,,,1' [0mm 00 ,’; ”WWW/14'Ila/11,1 ,,,,,.. 00: 5% my...“ may/ul/l/I/gfjer 57 1 00:00 Day 51 100-1001 48 Cortisol 00 day I ”W; Mun/W/MM”, 00: of -"-/////// 45 time SUBJID 44.4”” “aw/7111!,” 00 Mum/1. '