Treatment of irritability in subjects with autism spectrum disorder with moderate to severe anxiety and / or social avoidance

Abstract

The present technology relates to a method of treating one or more behavioral symptoms of autism spectrum disorder (ASD) in a subject by administering an effective amount of cannabidiol (CBD). Specifically, subjects with moderate to severe ASD and relatively high social avoidance and / or anxiety are more likely to exhibit reduced excitability when treated with CBD.

Description

[Technical field]

[0001] The present disclosure relates to a method of treating irritability in a subject diagnosed with autism spectrum disorder (ASD) by administering to the subject an effective amount of cannabidiol (CBD), wherein the irritable symptoms of ASD are treated in the subject. [Background technology]

[0002] Autism spectrum disorders (ASD) are generally characterized by several neurodevelopmental disorders, such as communication and socialization difficulties (e.g., social avoidance / withdrawal), as well as rigid and repetitive behaviors. "Problem behaviors" are also very common in ASD and may be more severe in ASD compared to typical development than in neurodevelopmental disorders. Problem behaviors include self-injury, outbursts, aggression, property damage, inappropriate behavior / language, and irritability. In addition, many children diagnosed with ASD meet the criteria for anxiety disorders. For children diagnosed with ASD, problem behaviors may be difficult for adult caregivers to manage. (See O'Nions et al. "How do Parents Manage Irritability, Challenging Behavior, Non-Compliance, and Anxiety in Children with Autism Spectrum Disorders? A meta-Synthesis" J. of Autism and Developmental Disorders (2018) 48:1272-1286). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] O'Nions et al. “How do Parents Manage Irritability,Challenging Behavior,Non-Compliance,and Anxiety in Children with Autism Spectrum Disorders?A meta-Synthesis”J.of Autism and Developmental Disorders(2018)48:1272-1286 Summary of the Invention [Problem to be solved by the invention]

[0004] Caregivers of children diagnosed with ASD typically deal with problem behavior by attempting to adapt the child's environment to avoid situations that may trigger the problem behavior. Another way to handle problem behavior is to anticipate the problem behavior and have strategies ready to handle it. However, these compromises rarely reduce the incidence of problem behavior. Thus, safe and effective treatments are needed to reduce problem behavior in children diagnosed with ASD. [Means for solving the problem]

[0005] Dealing with behavior problems in subjects diagnosed with moderate to severe ASD can be difficult for caregivers.One of such problem behaviors is high irritability.High irritability can be expressed as anger, frustration, pressure and self-deprivation.Frequent episodes of high irritability can lead to considerable challenges for caregivers.

[0006] Unexpectedly, it has been found that the response of excitability in patients diagnosed with moderate to severe ASD to treatment with CBD is enhanced in subjects with ASD symptoms and subjects with fragile X syndrome (FSX) who also show high social avoidance scores and / or high anxiety scores compared to the general population.Specifically, compared to the general population of subjects with ASD, about twice as many subjects who show high social avoidance scores, high anxiety scores, or both show improvement in excitability compared to subjects with lower avoidance and anxiety scores.These results indicate that the use of CBD for the treatment of excitability in subjects with ASD is particularly effective in the subset of these subjects who also show high anxiety and / or high social avoidance.

[0007] In embodiments, irritability in a subject diagnosed with autism spectrum disorder (ASD) can be treated by administering an effective amount of cannabidiol (CBD) to the subject. Administration of CBD improves the subject's irritability based on an ABC-C irritability score. In embodiments, the subject has an ABC-C irritability score of 12 or greater prior to treatment.

[0008] In another embodiment, a subject diagnosed with ASD may exhibit relatively high social avoidance and / or relatively high anxiety along with relatively high excitability. A subject diagnosed with moderate to severe ASD, in some embodiments, has an Autism Observation Scale (R), Second Edition (ADOS-2) comparison score of 3 or more. In some embodiments, a subject with relatively high social avoidance has an ABC-C social avoidance score of more than 5. In some embodiments, a subject with relatively high anxiety has a Parent Rated Anxiety Scale for ASD (PRAS-ASD) score of more than 25.

[0009] In embodiments, the CBD is synthetic CBD. Alternatively, the CBD can be crude or purified plant-derived CBD. The CBD can be administered orally or transdermally. In embodiments, the botanically derived CBD does not contain THC. The effective amount of CBD can be 250 mg / day, 500 mg / day, or 750 mg / day. In some embodiments, the effective amount of CBD can be administered once a day or twice a day.

[0010] In some embodiments, the subject has been diagnosed with Fragile X Syndrome (FXS) comorbid with ASD.

[0011] Advantages of the present invention will become apparent to those skilled in the art with the benefit of the following detailed description of the embodiments and upon reference to the accompanying drawings. [Brief description of the drawings]

[0012] [Figure 1] Plot of PRAS total score (baseline) versus ABC-C social avoidance subscale (baseline). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] While the invention may be susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. The drawings may not be to scale. It should be understood, however, that the drawings and detailed description are not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

[0014] As used herein, the term "treating" or "treatment" refers to the alleviation, amelioration, elimination, or alleviation of at least one symptom (such as a behavioral symptom) of a condition, disease, or disorder in a subject, such as a human, or the improvement in an identifiable measurement associated with the condition, disease, or disorder.

[0015] As used herein, the term "clinical efficacy" refers to the ability to produce a desired effect in humans as demonstrated through human clinical studies or trials.

[0016] As used herein, the term "cannabidiol" or "CBD" refers to cannabidiol (2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol), cannabidiol prodrugs, and pharma- ceutically acceptable salts, solvates, metabolites, and metabolic precursors thereof. CBD may be obtained and purified from plant material, or may be synthesized. Synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969) and Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), both of which are incorporated herein by reference. In a preferred embodiment, optically active (-)-CBD is used in the therapeutic treatments described herein.

[0017] As used herein, the term "transdermal administration" refers to contacting the skin of a patient or subject with a composition containing an active agent under conditions effective for the active agent to penetrate the skin.

[0018] Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior in approximately one million children and adolescents between the ages of 5 and 17 in the United States. ASD refers to a range of conditions characterized by anxiety, repetitive patterns of behavior, impairments in social communication, including verbal and nonverbal communication, and impairments in developing and maintaining relationships. Although autism may be diagnosed at any age, symptoms generally appear during the first two years of life, and therefore it is referred to as a "developmental disorder." Research suggests that genes, acting together with environmental influences, may affect development leading to ASD. Furthermore, new research suggests that ASD is associated with disruptions to the endocannabinoid system.

[0019] Typically, the severity of ASD symptoms in a subject can be determined by observing the person's behavior and development. To assist clinicians in measuring the severity of ASD behavior symptoms, several behavioral tests have been developed. Exemplary tests for assisting clinicians in determining the severity of ASD symptoms include, but are not limited to, the following tests: Anxiety, Depression, and Mood Scale (ADAMS), Aberrant Behavior Checklist (ABC), Aberrant Behavior Checklist-Community (ABC-C), Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revisions (DSM-5-TR) and Autism Diagnostic Observation Scale-2nd Edition (ADOS-2).

[0020] The Anxiety, Depression, and Mood Scale (ADAMS) is a behavioral test used by clinicians, physicians, and researchers to assess anxiety, depression, and mood levels in patients with intellectual disabilities, including ASD. The ADAMS test consists of questions grouped into five subscales, including (i) general anxiety, (ii) social avoidance, (iii) obsessive-compulsive behavior, (iv) manic / hyperactive behavior, and (v) depressed mood. Each question is answered by the clinician / physician on a four-point scale ranging from 0 ("no problems") to 3 ("severe problems"). The ADAMS yields a total score in addition to the subscale scores.

[0021] Another test that clinicians can use to measure the severity of ASD symptoms is the Aberrant Behavior Checklist-Community test (ABC-C). The original Aberrant Behavior Checklist (ABC) was designed to assess behavioral concerns of adults in an institutional setting. The original ABC was later adapted to address non-institutionalized patients, specifically subjects diagnosed with ASD. The Aberrant Behavior Checklist-Community (ABC-C) is used by clinicians, physicians, and researchers to access specific behaviors in non-institutionalized patients with ASD. The original ABC-C test has five subscales, including (i) irritability, (ii) hyperactivity, (iii) social withdrawal, (iv) stereotypic behaviors, and (v) inappropriate speech. The ABC-C scale, like the ADAMS, is a four-point Likert-type scale ranging from 0 (no problems) to 3 (severe problems). The ABC-C Irritability subscale was used as the basis for the approval of two atypical antipsychotics indicated for ASD. Using the same questions but adding a subscale for social avoidance and splitting the scoring into six subscales, FXS (ABC-C FXS A modified score of the ABC-C was created to better assess behavior in subjects diagnosed with personality disorder.

[0022] The present disclosure also relates to a method of treating an irritable symptom of an autism spectrum disorder (ASD) in a subject by administering to the subject an effective amount of cannabidiol (CBD), wherein the irritable symptom of the ASD is treated in the subject, the method comprising transdermally administering to the subject an effective amount of cannabidiol (CBD).

[0023] In embodiments, the method can be used to treat irritability in subjects with moderate to severe ASD. Subjects with moderate to severe ASD have a comparison score of 3 or greater on the Autism Diagnostic Observation Scale (R) Second Edition (ADOS-2).

[0024] Generally, a subject experiencing "high excitability" will experience greater excitability than the average excitability of the relevant general population. Excitability can be determined using a scale such as the ABC-C excitability subscale. A subject requiring treatment for high excitability will have a high ABC-C excitability score. As used herein, the term "high ABC-C excitability score" refers to an ABC-C excitability score of more than 12, more than 13, more than 14, more than 15, more than 16, more than 17, more than 18, more than 19, or more than 20.

[0025] In general, subjects who experience "high social avoidance" will experience greater social avoidance than the average social avoidance of the relevant general population. FXS A subject with "high" social avoidance can be determined using a scale such as the social avoidance subscale. Subjects with "high" social avoidance have an ABC-C score of greater than 5, greater than 6, greater than 7, greater than 8, or greater than 9. FXS Has a social avoidance score.

[0026] Generally, a subject who experiences "high anxiety" will experience more anxiety than the average anxiety of the relevant general population.Anxiety can be measured using a scale such as the Parent-Rated Anxiety Scale for ASD (PRAS-ASD).A subject with "high" anxiety has a PRAS-ASD score of more than 25, more than 30, more than 35, more than 37, more than 40, or more than 45.

[0027] It should be understood that the scores used to determine high irritability, high anxiety and high social avoidance are used to show association with statistical data and clinical evaluation by physicians. The scores described that relate to higher than normal behavior (e.g., high irritability, high social avoidance and high anxiety) are population estimates obtained from studies that show that clinical evaluation of such behaviors is associated with these scores, but this is not necessarily an absolute threshold. Therefore, it should be understood that physicians do not necessarily rely on specific scores related to irritability, social avoidance and anxiety to determine whether a patient will benefit from pharmaceutical treatment. Rather, the use of clinical evaluation allows physicians to conclude that a subject will experience high irritability, high social avoidance and high anxiety, regardless of whether specific scores related to behaviors are determined.

[0028] Therapeutic agents have been developed that utilize innovative transdermal technologies that allow for sustained and controlled delivery of therapeutic levels of CBD. Transdermal cannabidiol delivery systems are taught in U.S. Patent Nos. 8,449,908 and 8,435,556, both of which are incorporated herein by reference.

[0029] Transdermal delivery of cannabinoids (e.g., CBD) has advantages over oral administration because it allows the drug to be absorbed directly into the bloodstream through the skin. This avoids first-pass hepatic metabolism, potentially allowing lower dosage levels of the active pharmaceutical ingredient to be effective with higher bioavailability and improved safety profiles. Transdermal delivery also avoids the gastrointestinal tract, reducing GI-related adverse events and the chance of potential degradation of CBD to THC by gastric acid, which may be associated with undesirable psychoactive effects. Additionally, transdermal delivery of CBD reduces the intensity and frequency of somnolence as an adverse event that is typically present with oral administration of CBD. Transdermal delivery of CBD can avoid the adverse events of liver function that are typically present with oral administration of CBD. In some embodiments, transdermal administration of an effective amount of CBD reduces the intensity of at least one adverse event by about 15% to about 95% compared to oral administration of CBD.

[0030] An effective amount of CBD can be about 50 mg to about 1000 mg per day. In some embodiments, an effective amount of CBD starts at about 50 mg per day and is gradually increased to about 750 mg per day. An effective amount of CBD can start at about 50 mg per day and is gradually increased to about 250 mg per day, 500 mg per day, 750 mg per day, or 1000 mg per day. In some embodiments, an effective amount of CBD starts at 250 mg per day. An effective amount of CBD can start at 500 mg per day. An effective amount of CBD can start at 750 mg per day. An effective amount of CBD can start at 1000 mg per day. In some embodiments, a daily dosage of about 250 mg is administered to a patient weighing 35 kg or less. In some embodiments, a daily dosage of about 500 mg is administered to a patient weighing more than 30 kg and less than or equal to 50 kg. In some embodiments, a daily dose of about 750 mg is administered to a patient weighing more than 50 kg. CBD can be administered in a single daily dose or in two daily doses. In some embodiments, an effective amount of CBD can be 390 mg in a divided daily dose.

[0031] The CBD may be in the form of a gel and may be pharma- ceutical manufactured as a clear, permeation-enhancing gel designed to provide controlled drug delivery transdermally in a once or twice daily administration. The CBD gel may be 1% (wt / wt) CBD to 7.5% (wt / wt) CBD. The CBD gel may have, for example, 4.2% (wt / wt) CBD or 7.5% (wt / wt) CBD. The CBD gel may be applied topically by the patient or a caregiver to the patient's upper arms and shoulders, back, thighs, or any combination thereof.

[0032] The CBD gel may include diluents and carriers, as well as other conventional excipients such as wetting agents, preservatives, and suspending and dispersing agents.

[0033] The CBD gel may include solubilizers, permeation enhancers, solubilizers, antioxidants, bulking agents, thickeners, and / or pH adjusters. The composition of the CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (wt / wt) of the composition, b. a lower alcohol having 1-6 carbon atoms present in an amount of about 15% to about 95% (wt / wt) of the composition, c. a first penetration enhancer present in an amount of about 0.1% to about 20% (wt / wt) of the composition, and d. water in an amount sufficient to make the composition total 100% (wt / wt). Other formulations of CBD gels may be found in WO 2010 / 127033, the entire contents of which are incorporated herein by reference.

[0034] In some embodiments, the transdermal preparation may be a cream, salve, or ointment. The CBD may be delivered by a bandage, pad, or patch. The CBD may be administered transdermally to the subject's upper arm and shoulder. In some embodiments, the CBD is administered transdermally to the subject's thigh or back. The CBD may be synthetic CBD. The CBD may be purified CBD. The CBD may be derived from a plant.

[0035] In some embodiments, the CBD is administered in a pharma- ceutically acceptable preparation that does not contain THC. In some embodiments, the CBD is administered without THC or any other extract of cannabis. In some embodiments, the CBD is synthetic CBD. In some embodiments, it is an extract. In some embodiments, it is purified.

[0036] The alleviation of irritability in a subject diagnosed with autism spectrum disorder (ASD) may include an improvement in ABC-C irritability score. Irritability may be measured using ABC-C irritability subset score. A high irritability in a subject may be indicated when the ABC-C irritability score is 18 or more. In an embodiment, an improvement in ABC-C irritability score is indicated when the subject's ABC-C irritability score is less than 18, or less than 17, or less than 16, or less than 15, or less than 14, or less than 13, or less than 12, or less than 11, or less than 10, or less than 9, or less than 8, or less than 7, or less than 6, or less than 5, or less than 4, or less than 3, or less than 2, or less than 1, or equal to 0 after treating the subject with CBD. In embodiments, an improved ABC-C excitability score is indicated if the subject's ABC-C excitability score decreases by at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least 18 after treatment with CBD. In embodiments, an improved ABC-C excitability score is indicated if the subject's ABC-C excitability score decreases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% after treatment with CBD.

[0037] Reducing irritability in a subject diagnosed with moderate to severe ASD can also include improving the Anxiety, Depression and Mood Scale (ADAMS) total score. In some embodiments, reduc- ing one or more behavioral symptoms of ASD can include improving one or more subscales of the ADAMS.

[0038] In some embodiments, the subject is also administered one or more additional medications, which in some embodiments are selected from the group consisting of antidepressants, anti-anxiety medications, alpha-2-adrenergic agonists, psychostimulants, antipsychotics, and combinations thereof.

[0039] In some embodiments, the one or more additional drugs include an antipsychotic. Examples of antipsychotics typically administered to subjects diagnosed with ASD include, but are not limited to, risperidone, aripiprazole, haloperidol, olanzapine, ziprasidone, and quetiapine fumarate in some embodiments.

[0040] In some embodiments, the one or more additional medications comprise an alpha-2-adrenergic agonist. Examples of alpha-2-adrenergic agonists typically administered to subjects diagnosed with ASD include, but are not limited to, clonidine and guanfacine.

[0041] In some embodiments, one or more additional drugs include antidepressants.For example, selective serotonin reuptake inhibitor (SSRI) antidepressants can also be administered to the subject as additional drugs.The examples of SSRIs used for the subject with ASD include, but are not limited to, fluoxetine, citalopram and escitalopram.

[0042] In some embodiments, the one or more psychotropic drugs include a stimulant drug. Examples of stimulant drugs typically administered to subjects diagnosed with ASD include, but are not limited to, methylphenidate HCl, atomoxetine HCl, dexfetamine, and disdexfetamine mesylate.

[0043] Unexpectedly, it has been found that the treatment of irritability in subjects diagnosed with ASD is enhanced when the patient has a high social avoidance score and / or a high anxiety score. Typically, the severity of symptoms in ASD patients is determined using the ABC-C test. As mentioned above, the ABC-C test has five subscales, including (i) irritability, (ii) hyperactivity, (iii) social withdrawal, (iv) stereotypic behavior, and (v) inappropriate speech. In order to better evaluate the behavior of subjects diagnosed with FXS, the ABC-C test is used to measure the severity of symptoms in subjects diagnosed with FXS. FXS Test created: ABC-C FXS The test uses the same questions as the ABC-C test, but adds a subscale for social avoidance, dividing the scoring into six subscales. FXS If the test applies to subjects with ASD (but not a diagnosis of FXS), then the ABC-C FXS This unique application of the test results in a novel separation of subjects based on a criterion (i.e., social avoidance) that has not previously been used to study subjects with ASD. FXS When applying the test, ABC-C exceeding 7 FXS Subjects with a social avoidance score were assessed using an ABC-C score of 7 or less. FXS The study found that subjects with ASD showed a two-fold improvement in irritability compared to subjects with social avoidance scores. FXS ) is associated with a preferential positive response to treatment with CBD in patients with high ABC-C FXS Irritability was found in subjects with social avoidance scores.

[0044] Subjects with a Parent Rated Anxiety Scale (PRAS) score greater than 37 were found to show a two-fold improvement in irritability compared to subjects with a PRAS score of 37 or less.

[0045] In some embodiments, the subject may be diagnosed with Fragile X Syndrome (FXS) comorbid with moderate to severe ASD. Similar to subjects with a diagnosis of ASD, patients diagnosed with FXS and ASD show improved irritability when treated with CBD, particularly transdermal CBD. It has been found that FXS subjects with high social avoidance scores and / or high anxiety scores also show the same improved reduction in irritability as seen in ASD patients without FXS. EXAMPLES

[0046] [Example 1] Treatment of ASD – the BRIGHT Trial An exploratory open-label safety, tolerability and efficacy study of Zygel™ ZYN002 transdermal gel was conducted in 37 children and adolescents with autism spectrum disorder. The patient population (ages 4-17) was primarily patients with moderate to severe ASD. ASD was confirmed by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria to evaluate the safety and efficacy of ZYN002 in treating ASD-related behaviors, as measured by various efficacy assessments. These included the Aberrant Behavior Checklist-Community (ABC-C), Autism Diagnostic Observation Scale®, 2nd Edition (ADOS-2), and Parent-Rated Anxiety Scale for ASD (PRAS-ASD). ZYN002 was administered to patients with moderate to severe symptoms of ASD as an add-on to standard of care.

[0047] Patient demographics. The majority of patients were male (92%) and the mean age was 9.2 years. Patient weights ranged from 15 to 108 kilograms (mean = 41.6, median = 30.2). The mean time to diagnosis in this population was 5.4 years. Most patients had moderate or severe ASD at baseline as measured by ADOS®-2 comparison scores (94%) and Diagnostic and Statistical Manual of Mental Disorders, 5th Edition severity level (92%). The mean ABC-C irritability score was 30.3, and nine patients (24.3%) had PRAS-ASD scores indicative of possible clinical anxiety, further highlighting the severity of symptoms in the enrolled patient population.

[0048] The majority of patients (92%) participated in the study using at least one underlying medication. 65% of patients were taking at least one psychotropic medication, such as antidepressants, anxiolytics, and antipsychotics. Of the 37 subjects, 14 were taking antipsychotics, 11 were taking risperidone, 1 was taking haloperidol, 1 was taking olanzapine, and 1 was taking quetiapine fumarate. Sixteen subjects were taking stimulant medications used for ADHD and inotropes, including clonidine (6), guanafacine (5), methylphenidate HCl (7), atomoxetine HCl (2), dexamethasone (1), and lysemide mesylate (2).

[0049] protocol Subjects were administered a total daily dose of CBD of 250 or 500 mg. It was administered in the form of ZYN002 CBD transdermal gel twice daily for 14 weeks. After completing dosing during the 14-week period, eligible participants were given the option to enroll in a 6-month extension study. The study evaluated multiple efficacy assessments including ABC-C, PRAS-ASD, Autism Parenting Stress Index, Autism Impact Measure (AIM), and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I). The ABC-C Irritability subscale was used as the basis for approval of two atypical antipsychotics (risperidone and aripiprazole) indicated for ASD.

[0050] result The ABC-C as well as all five subscales of the Parent-Rated Anxiety Scale for ASD (PRAS-ASD) showed both statistically significant and clinically significant improvement at 14 weeks of treatment versus baseline.

[0051] Table 1 summarizes the 14-week improvements from each subscale of the ABC-C. All results were statistically significant; p<0.001 for all subscales.

[0052] [Table 1]

[0053] There was a 40% improvement in stereotyped behavior on the ABC scale, a 33% improvement in repetitive behavior on the Parent Raported Anxiety Scale, and an unexpected overall improvement in children with this severity of ASD who were also taking antipsychotic medications. Results were both statistically and clinically significant.

[0054] Other efficacy outcomes reinforce the findings demonstrated in ABC-C. For example, ZYN002 patients experienced a mean improvement of 46% at week 14 from a baseline score of 40.8 as measured by the PRAS-ASD (p<0.001), and 57% of patients were rated as very much or greatly improved at week 14 as measured by the Clinical Global Impressions-Improvement (CGI-I).

[0055] ZYN002 was well tolerated in this study, with no serious adverse events (SAEs) reported. Twenty-eight patients completed the 14-week study. This rate of discontinuation is consistent with other trials in ASD. Only one patient was lost to follow-up and had no post-treatment efficacy assessment. Less than half of the patients (49%) experienced any adverse events (unrelated or related to study drug), all of which were mild (75%) or moderate (25%). Only 14% of patients experienced adverse events considered related to treatment, all of which were related to the application site, and most were mild and transient. No serious adverse events were reported during the study. Eighteen patients who completed the BRIGHT study enrolled in an open-label extension.

[0056] result The ABC-C and all five subscales of the Parent-Rated Anxiety Scale for ASD (PRAS-ASD) showed both statistically significant and clinically significant improvement at 14 weeks of treatment versus baseline. Table 1 summarizes the ABC-C results at weeks 6 and 14.

[0057] [Example 4] Treatment of irritability in subjects Data from the aforementioned study showed that administration of transdermal CBD had a significant improvement in irritability scores in subjects diagnosed with moderate to severe ASD. A summary of the results of study completers (N=28) from an open-label safety, tolerability and efficacy study of Zygel™ ZYN002 transdermal gel (see Example 1) is shown in Table 1.

[0058] Data collected from the study presented herein and other similar studies were pooled together and analyzed. Table 2 shows a summary of the pooled data collected from 156 subjects. Subjects had a baseline ABC-C irritability score of 18 or higher. Subjects had moderate to severe symptoms of ASD (ADOS-2, comparison score of 5 or higher). Data shown in Table 2 is the change in ABC-C irritability at week 12 for all patients. In previous studies (e.g., presented in Example 1, Table 1), data was enriched by removing non-completers from the analysis and presenting only data from completers. The current analysis in Table 2 shows that, without data enrichment, Zygel™ ZYN002 transdermal gel provided minimal improvement in ABC-C irritability in patients with FXS and comorbid ASD compared to placebo.

[0059] [Table 2]

[0060] Data presented in Table 2 are based on baseline ABC-C irritability scores of 18 or more and ABC-C scores of 7 or more. FXS These results were further analyzed by restricting the data to subjects with a baseline ABC-C irritability score of 18 or greater and an ABC-C score of 7 or less. FXS The results of this analysis are shown in Table 3. The data show that patients with an ABC-C score of more than 7 FXS Subjects with social avoidance scores of 7 or less were assigned an ABC-C score of 7 or less. FXS These results show that subjects with low social avoidance scores had a much better response to transdermal CBD administration than subjects with low social avoidance scores.

[0061] [Table 3]

[0062] Additionally, data from the BRIGHT trial of ASD showed that baseline anxiety scores on the Parent-Rated Anxiety Scale for ASD (PRAS-ASD) correlated with the ABC-C FXS Figure 1 shows the PRAS total score (baseline) vs. the ABC-C score. FXS Figure 1 shows a plot of the Social Avoidance subscale (Baseline). The data shows the correlation between Social Avoidance and Anxiety with a correlation coefficient of 0.45526 (P value = 0.005).

[0063] This led to further analysis of the Zygel™ ZYN002 transdermal gel data to determine the effect of Zygel on ABC-C irritability scores in subjects with high PRAS-ASD anxiety scores (>37). This analysis, presented in Table 4, shows that subjects with baseline ABC-C irritability scores of 18 or greater and PRAS-ASD scores of >37 showed better improvement in irritability compared to subjects with PRAS-ASD scores of 37 or less. The improvement in irritability in subjects with high PRAS-ASD scores is summarized in Table 4. Note that subjects in Period 2 were Period 1 responders (defined as 35% or greater improvement in ABC-C irritability scores from Period 1 baseline to Week 14) and therefore may have a significantly greater change as a result than all Period 1 subjects.

[0064] [Table 4]

[0065] Taken together, this data indicates that subjects with moderate to severe ASD and relatively high social avoidance and / or anxiety are more likely to show reduced excitability when treated with CBD.

[0066] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. This description should therefore be interpreted as illustrative only and for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It should be understood that the forms of the invention shown and described herein should be interpreted as examples of embodiments. Elements and materials may be substituted from those shown and described herein, parts and steps may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. 1. A pharmaceutical composition for use in a method for treating irritability in a subject diagnosed with autism spectrum disorder (ASD), comprising: The method includes administering to the subject an effective amount of cannabidiol (CBD); the pharmaceutical composition comprises cannabidiol (CBD); the subject has a high baseline ABC-C irritability score, and The subject also had a high baseline ABC-C ＦＸＳ have a high baseline social avoidance score and / or a high Parent Rated Anxiety Scale for ASD (PRAS-ASD) score; Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1, wherein the subject has a baseline ABC-C excitability score greater than 12.

3. Subjects must have a baseline ABC-C score greater than 5. ＦＸＳ The pharmaceutical composition of claim 1, having a social avoidance score.

4. 10. The pharmaceutical composition of claim 1, wherein the subject has a baseline Parent-Rated Anxiety Scale for ASD (PRAS-ASD) score greater than 25.

5. 10. The pharmaceutical composition of claim 1, wherein the subject has been diagnosed with moderate to severe ASD.

6. 10. The pharmaceutical composition of claim 1, wherein the subject has an Autism Diagnostic Observation Scale-Second Edition (ADOS-2) comparison score of 3 or greater.

7. 10. The pharmaceutical composition of claim 1, wherein the CBD is administered transdermally.

8. 2. The pharmaceutical composition of claim 1, wherein the CBD is synthetic CBD.

9. 2. The pharmaceutical composition of claim 1, wherein the CBD is plant-derived CBD.

10. 10. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is a total daily dose of 250 mg.

11. 10. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is a total daily dose of 500 mg.

12. 10. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is a total daily dose of 750 mg.

13. 10. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is a total daily dose of 1000 mg.

14. 10. The pharmaceutical composition of claim 1, wherein the effective amount is administered twice daily.

15. 10. The pharmaceutical composition of claim 1, wherein the CBD is administered in a pharmaceutically acceptable preparation that does not contain THC.

16. 10. The pharmaceutical composition of claim 1, wherein the subject has also been diagnosed with Fragile X Syndrome (FXS).

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