Treating sleep difficulties in patients with autism spectrum disorder

Abstract

The present invention relates generally to the treatment of autism spectrum disorders (ASD) and sleep difficulties, and more particularly to treating sleep disorders and / or improving daytime functioning in ASD patients with tasimelteon.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 243,918, filed September 14, 2021, co-pending U.S. Provisional Patent Application No. 63 / 268,430, filed February 23, 2022, and co-pending U.S. Provisional Patent Application No. 63 / 269,137, filed March 10, 2022, each of which is incorporated herein by reference in its entirety as if fully set forth herein. [Background technology]

[0002] Autism spectrum disorder Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with persistent deficits in social communication and restricted / repetitive behaviors, among other criteria. ASD comprises a range of manifestations and levels of severity that may require minimal to substantial support.

[0003] Symptoms of ASD include those that affect social communication and interaction and restricted or repetitive behaviors or interests. Known symptoms of ASD include, for example, avoidance of or inability to maintain eye contact; lack of facial expression; reduced use of gestures, including hand gestures; less shared interests with others; not pointing or looking where others are pointing; not noticing when others are hurt or sad; not pretending in play; lack of interest in peers; difficulty understanding the feelings of others or discussing their own; inability to play games that involve taking turns; lining up objects when upset or when the order of objects has been changed; difficulty learning words or frames; These include: repetitive sounds (echolalia); playing with a toy in the same way every time; focusing on parts of an object; being upset by small changes; obsessive interests; abnormal attachment to routine; hand flapping; rocking; spinning in circles; abnormal reactions to sounds, smells, tastes, sights or touch; delayed language skills; delayed motor skills; delayed cognitive or learning skills; hyperactive, impulsive and / or inattentive behaviour; epilepsy or seizure disorders; abnormal eating or sleeping habits; difficulty sleeping or daytime functioning; gastrointestinal problems; unusual moods or emotional responses; anxiety, stress or excessive worry; and absence of fear or being more frightened than expected.

[0004] The prevalence of insomnia in individuals with ASD has been documented to be up to 80%, which is higher than in healthy control subjects. Sleep complaints in ASD are diverse. However, difficulty falling asleep and restlessness / nighttime awakenings repeatedly emerge as major sleep-related problems for individuals with ASD. One or more such sleep complaints may lead to reduced sleep time with attendant consequences on daytime functioning, including worsening of other ASD symptoms. Although most sleep-related research in ASD has focused on children, a growing body of research appears to indicate that sleep is similarly disturbed in adults with ASD.

[0005] Although the etiology of sleep disorders in ASD remains an active area of ​​research, there is evidence to suggest that circadian abnormalities may be a significant contributor to sleep-related symptoms in ASD. Serum melatonin levels are significantly reduced in ASD participants compared to healthy controls.

[0006] Recent evidence suggests a genetic cause for these abnormalities with disruption of the serotonin-N-acetylserotonin-melatonin pathway with polymorphisms identified in the acetylserotonin O-methyltransferase (ASMT) gene. In addition to abnormal melatonin levels detected in individuals with ASD, mutations in regulatory genes controlling the expression of melatonin receptors MTNR1A and MTNR1B are known. Taken together, these studies suggest that melatonin synthesis and signaling may be abnormal in ASD and contribute to producing sleep-related symptoms. At present, there are no approved treatments for sleep symptoms in ASD.

[0007] Smith-Magenis Syndrome (SMS) Smith-Magenis syndrome (SMS) is caused by an interstitial deletion at 17p11.2 or, more rarely, a variant in the retinoic acid-inducible 1 (RAI1) gene. The prevalence of SMS is estimated to be between 1 in 15,000 and 1 in 25,000. Haploinsufficiency of RAI1 is the primary cause of the neurobehavioral and metabolic phenotype in SMS. Individuals with SMS present with a distinct pattern of mild to moderate intellectual disability, delayed speech and language skills, distinctive craniofacial and skeletal abnormalities, behavioral disorders, and, almost uniformly, significant sleep difficulties. RAI1 copy number alterations have also been associated with several neurodevelopmental disorders, including ASD.

[0008] Tasimelteon As a circadian regulator, tasimelteon is a dual melatonin receptor agonist approved in the United States under the trade name HETLIOZ® for the treatment of non-24-hour sleep-wake disorder (Non-24) and difficulty sleeping at night in Smith-Magenis syndrome (SMS). Tasimelteon has been shown to be safe and well tolerated in previous clinical trials in healthy volunteers, participants with primary insomnia, Non-24 participants, and pediatric participants with SMS.

[0009] Tasimelteon has a higher affinity for the MT2 receptor than for the MT1 receptor. In the dose range of 3 mg to 300 mg, the pharmacokinetics of tasimelteon are linear. The absolute bioavailability of tasimelteon is 38%, and its peak plasma concentration (t max Liquid formulations of tasimelteon and methods for administering same are described in International Patent Application Publication No. WO / 2021 / 119456, which is incorporated herein as if fully set forth herein. Summary of the Invention

[0010] In one embodiment, the present invention provides a method of treating a patient suffering from an autism spectrum disorder (ASD), comprising administering to the patient a dose of tasimelteon effective to ameliorate at least one symptom of ASD.

[0011] In another embodiment, the present invention provides a method of treating a patient suffering from sleep difficulties associated with an autism spectrum disorder (ASD), comprising administering to the patient a dose of tasimelteon effective to improve sleep, daytime functioning, or both.

[0012] In yet another embodiment, the present invention provides an improvement in a method of improving sleep in a patient consisting essentially of administering to said patient an amount of tasimelteon effective to improve sleep, comprising the step of selecting a patient for said treatment by identifying said patient as suffering from sleep difficulties associated with an autism spectrum disorder (ASD).

[0013] In one embodiment, the present invention provides a method of treating a patient suffering from an autism spectrum disorder (ASD), comprising determining or otherwise identifying that the patient possesses one or more variants in the retinoic acid inducible 1 (RAI1) gene associated with reduced RAI1 function; and if the patient possesses one or more of said variants, administering to the patient a dose of tasimelteon effective to alleviate sleep difficulties experienced by the patient.

[0014] In another embodiment, the present invention provides an improvement in a method for treating sleep difficulties in a patient, comprising the step of selecting as said patient a person carrying at least one variant of the retinoic acid inducible 1 (RAI1) gene associated with reduced RAI1 function. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In studies evaluating the efficacy of tasimelteon in treating sleep difficulties in ASD, patients were selected for treatment based on a diagnosis of ASD and a recent history of sleep difficulties defined as a sleep onset latency of at least 45 minutes for at least 3 nights per week and continuing for at least 3 months. Those patients whose sleep difficulties could be attributed to another diagnosable disorder or medication were excluded, as were patients who tested positive for sleep apnea or had symptoms suggestive of sleep apnea.

[0016] Large-scale association studies of the ASD MSSNG database have revealed many findings that may have important implications for the treatment of ASD. The ASD MSSNG database contains the genomes of over 11,000 individuals representing over 4,000 families. Approximately half of those represented in the ASD MSSNG database are affected by ASD.

[0017] This analysis reveals one example of a 17p11.2 deletion known to cause SMS and three additional microdeletions in RAI1 exon 3. In addition, this analysis reveals 53 RAI1 missense variants, two frameshift variants and one splicing variant.

[0018] Table 1 below provides details of each of these missense, frameshift and splicing variants, including start and end positions; the wild type or reference allele and alternative allele; where applicable, details of the location of the variant within the RAI1 gene and the resulting protein sequence change; and the predicted effect in terms of RAI1 function. All references to start and end positions and wild type or reference alleles are for the RAI1 transcript NM030665.3 (available at: https: / / databases.lovd.nl / shared / refseq / RAI1_NM_030665.3_codingDNA.html).

[0019] [Table 1] JPEG2024531569000002.jpg66149

[0020] The presence of one or more of the variants in Table 1 in the genome of an individual with ASD is predicted to result in some degree of reduction in RAI1 gene function, possibly up to loss of function of the gene. An individual is considered to carry one or more of the variants in Table 1 if they are heterozygous, homozygous, or compound heterozygous for any of the variants in Table 1.

[0021] As mentioned above, haploinsufficiency of RAI1 is the primary cause of neurobehavioral and metabolic symptoms in patients with SMS, with significant sleep difficulties being the most common symptom. The currently prevailing theory is that there is an underlying circadian pathophysiology that causes sleep difficulties in SMS associated with RAI1 haploinsufficiency. These patients have low overall melatonin concentrations and abnormal timing of peak plasma melatonin concentrations. This abnormal melatonin rhythm is estimated to occur in 95% of patients with SMS.

[0022] However, both ASD and SMS patients suffer from sleep difficulties, and various aspects of sleep difficulties seen in SMS patients may overlap in ASD patients, particularly those with significant variants in the RAI1 gene, such as those identified in Table 1 or deletions of 17p11.2.

[0023] Thus, embodiments of the present invention are directed to treating sleep difficulties in ASD patients carrying one or more variants associated with reduced RAI1 function. Treating sleep difficulties can be assessed directly and / or in terms of improved daytime functioning, as further described below.

[0024] According to some embodiments, ASD patients determined to carry one or more such variants are orally administered tasimelteon once a day, approximately one hour before bedtime. In all cases, tasimelteon is administered under fasting conditions, including administering tasimelteon without food and administering tasimelteon after a period in which the patient has not consumed food. Administration of tasimelteon under fasting conditions is described in U.S. Patent No. 10,376,487, which is incorporated herein as if fully set forth herein.

[0025] Dosing is based on age and / or weight. Adult patients and pediatric patients weighing 28 kg or more receive 20 mg of tasimelteon in either capsule or oral suspension (4 mg / mL). Pediatric patients weighing less than 28 kg receive 0.7 mg / kg of tasimelteon in oral suspension (4 mg / mL). Patients 16 or 17 years of age weighing 28 kg or more receive either the 20 mg capsule or the 4 mg / mL oral suspension, depending on the patient's preference.

[0026] The efficacy of treatment with tasimelteon is assessed in terms of improvement in sleep difficulties and / or improved daytime functioning using one or more known scales: Patient Global Impression-Change (PGI-C) scale, Patient Global Impression-Change Behavior (PGI-C Behavior) scale, Clinical Global Impression-Severity (CGI-S) scale, Clinical Global Impression-Change (CGI-C) scale, daily electronic diary, Aberrant Behavior Checklist (ABC).

[0027] The PGI-C is a 7-point rating scale on which participants or their guardians rate the improvement of the participant's symptoms compared to the start of the study, with ratings given as follows: 1. very improved, 2. much improved, 3. slightly improved, 4. no change, 5. slightly worse, 6. much worse, or 7. very worse.

[0028] The PGI-C Behavior is a similar 7-point scale on which participants or their guardians rate the improvement of participants' behavioral problems compared to the beginning of the study.

[0029] The CGI-S is a similar 7-point rating scale on which the study physician rates the severity of the participant's condition at the time of evaluation, relative to the physician's own previous experience with participants with the same diagnosis. Ratings are given as follows: 1. Not at all ill, normal; 2. Borderline, not ill, 3. Mildly ill, 4. Moderately ill, 5. Very ill, 6. Severely ill, or 7. Extremely ill.

[0030] The CGI-C is a similar 7-point rating scale on which investigators rate participants' improvement in symptoms compared to the start of the study, with ratings given as: 1. very much improved, 2. much improved, 3. slightly improved, 4. no change, 5. slightly worse, 6. much worse, or 7. very worse.

[0031] The daily electronic diary consists of questionnaires to be completed daily by the participant or caregiver, including a sleep diary and additional questionnaires such as post-sleep and pre-sleep questionnaires reporting, for example, the participant's sleep onset and wake-up times, evaluation of nighttime sleep, daytime sleep episodes, etc. These questionnaires may include the PGI-S Behavior scale, a 5-point rating scale on which the participant or their guardian rates the severity of the participant's behavioral problems at the time of the evaluation. The ratings are as follows: 0. none, 1. mild, 2. moderate, 3. severe, or 4. very severe.

[0032] A sleep diary, such as the daily electronic diary described above, may be used to assess various sleep parameters before, during and / or after treatment according to the invention, and changes in such parameters in response to treatment. For example, sleep onset and wake up times may be used to measure sleep duration before, during and / or after treatment according to the invention.

[0033] The ABC is a validated symptom checklist for parents and caregivers to assess problem behavior in children and adults. Its 58 items are divided into five subscales: (1) irritability / restlessness, (2) lethargy / social withdrawal, (3) stereotypy, (4) hyperactivity / noncompliance, and (5) inappropriate speech.

[0034] As will be appreciated by those skilled in the art, other methods of assessing the effectiveness of treatment can be used and are within the scope of the present invention. Improved sleep can include a decrease in sleep onset latency (SOL).

[0035] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. It is to be further understood that as used herein, the words "comprises" and / or "comprising" specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0036] This written description uses examples to disclose the invention together with the best mode and to enable those 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 that have insubstantial differences from the literal language of the claims.

Claims

1. A pharmaceutical composition for treating autism spectrum disorder (ASD), comprising tasimelteon, A pharmaceutical composition comprising tasimelteon in a dose effective to improve at least one symptom of ASD, the pharmaceutical composition being orally administered once daily before bedtime.

2. the at least one symptom of ASD is: Avoidance of eye contact or inability to maintain eye contact; lack of facial expression; a decreased use of gestures, including hand movements; Few shared interests with others; Not pointing or looking where others are pointing; Not noticing that others are hurt or sad; Don't pretend to be something in play; lack of interest in peers; Difficulty understanding the feelings of others or discussing one's own feelings; and Do not play games that involve taking turns 10. The pharmaceutical composition of claim 1, wherein the symptom affecting social communication or interaction is selected from the group consisting of:

3. The at least one symptom is Aligning objects when disturbed or when the order of objects is changed; Repeating words or phrases (echolalia); Playing with toys in the same way every time; Concentrating on a part of an object; Being upset by small changes; Obsessive interests; An abnormal attachment to routine; flapping hands; Rocking; Spinning around; and Abnormal reactions to sounds, smells, tastes, sights, or touch 2. The pharmaceutical composition of claim 1, wherein the symptom is a condition affecting restricted or repetitive behaviors or interests selected from the group consisting of:

4. The at least one symptom is delayed language skills; delayed motor skills; Delays in cognitive or learning skills; hyperactive, impulsive and / or inattentive behavior; epilepsy or seizure disorders; abnormal eating or sleeping habits; difficulty sleeping or daytime functioning; gastrointestinal problems; unusual moods or emotional reactions; Anxiety, stress or excessive worry; and Lack of fear or more fear than expected 2. The pharmaceutical composition of claim 1, selected from the group consisting of:

5. the improvement of at least one symptom is Clinical Global Impression of Change (CGI-C) scale; Clinical Global Impression of Severity (CGI-S) scale; Patient Global Impression of Change (PGI-C) scale; Abnormal Behavior Checklist (ABC), the Patient Global Impression of Severity of Behavior (PGI-S Behavior) scale; and Patient Global Impression of Behavioral Change (PGI-C Behavior) scale 10. The pharmaceutical composition of claim 1, comprising an improvement in at least one metric selected from the group consisting of:

6. A pharmaceutical composition for treating sleep difficulties associated with autism spectrum disorder (ASD), comprising tasimelteon, A pharmaceutical composition comprising tasimelteon in a dose effective to improve sleep, daytime function, or both, and administered orally once daily before bedtime.

7. Improved sleep, Clinical Global Impression of Change (CGI-C) scale; Clinical Global Impression of Severity (CGI-S) scale, and Patient Global Impression of Change (PGI-C) scale 7. The pharmaceutical composition of claim 6, comprising an improvement in at least one metric selected from the group consisting of:

8. Improved daytime functionality Abnormal Behavior Checklist (ABC), the Patient Global Impression of Behavioral Severity (PGI-S Behavior) scale, and Patient Global Impression of Behavioral Change (PGI-C Behavior) scale 7. The pharmaceutical composition of claim 6, comprising an improvement in at least one metric selected from the group consisting of:

9. 7. The pharmaceutical composition of claim 6, wherein the improved sleep comprises a decrease in sleep latency (SOL).

10. 7. The pharmaceutical composition of claim 6, wherein the sleep difficulty comprises a sleep onset latency of at least 45 minutes.

11. 7. The pharmaceutical composition of claim 6, wherein the dose of tasimelteon is 20 mg.

12. The pharmaceutical composition of claim 6, administered without food.

13. 7. The pharmaceutical composition of claim 6, wherein the dose of tasimelteon is 0.7 mg / kg.

14. A pharmaceutical composition for treating autism spectrum disorder (ASD) in a patient, comprising tasimelteon, the patient carries one or more variants in the retinoic acid-inducible 1 (RAI1) gene associated with reduced RAI1 function; A pharmaceutical composition wherein said one or more variants of the RAI1 gene are selected from the group consisting of the variants listed in Table 1 and 17p11.2 deletions.

15. 15. The pharmaceutical composition of claim 14, wherein the one or more variants comprise a frameshift variant.

16. The pharmaceutical composition of claim 15, wherein the frameshift variant is a GA to AGC mutation at positions 444 and 445 of the RAI1 sequence.

17. The pharmaceutical composition of claim 15, wherein the frameshift variant is a C to CA mutation at position 5221 of the RAI1 sequence.