Treatment of autism spectrum disorder with cannabidiol

Abstract

This invention provides a method for addressing one or more behavioral symptoms of autism spectrum disorder (ASD) in a given subject. [Solution] A method of treatment is provided in which an effective amount of cannabidiol (CBD) is administered transdermally to the target.

Description

Technical Field

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 029,899, filed on May 26, 2020, entitled "Treatment of Fragile X Syndrome and Autism Spectrum Disorder Using Cannabidiol", the content of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to a method of treating one or more behavioral symptoms of Fragile X syndrome in a subject by transdermally administering an effective amount of cannabidiol (CBD) to the subject, and 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) to the subject.

Background Art

[0003] Cannabinoids are a group of compounds contained in cannabis.

[0004] The two main cannabinoids contained in Cannabis are cannabidiol, i.e., CBD and Δ9-tetrahydrocannabinol, i.e., THC. CBD has no psychoactive effects of THC. Research has shown that CBD can be used to treat disorders such as epilepsy, arthritis, and cancer.

[0005] FXS is the most common genetic intellectual disability in males and a significant cause of intellectual disability in females. FXS is caused by a mutation in the fragile X mental retardation 1 (FMR1) gene located on the X chromosome, resulting in dysregulation of the endocannabinoid system, including a decrease in endocannabinoids (2-AG and anandamide [AEA]). This disorder negatively impacts synaptic function, plasticity, and neuronal connectivity, leading to a continuum of intellectual disability, social anxiety, and memory problems. In the United States, there are approximately 71,000 people with FXS.

[0006] "The most significant concerns reported by parents are often behavioral problems, and high levels of stress and depression, as well as low quality of life for parents, are usually associated with an increase in problematic behaviors in children." Wheeler A, Raspa M, Bann C, Bishop E, Hassl D, Sacco H, Bailey DB. 2014. "Anxiety attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome." Am J Med Genet Part A 164A:141~155, 141. "Consequently, mitigating behavioral problems is a primary focus of ongoing clinical trials investigating the efficacy of new medications for FXS." Wheeler, pp. 141-142.

[0007] The Anxiety, Depression, and Mood Scale (ADAMS) is a tool used by clinicians, physicians, and researchers to assess levels of anxiety, depression, and mood in patients with intellectual disabilities such as FXS. The ADAMS consists of questions grouped into five subscales: (i) generalized anxiety, (ii) social avoidance, (iii) obsessive-compulsive behaviors, (iv) manic / hyperactive behaviors, and (v) depressed mood. Clinicians / physicians respond to each question on a four-point scale ranging from 0 ("no problem") to 3 ("severe problem"). In addition to the subscale scores, the ADAMS generates an overall score.

[0008] The original Behavioral Abnormalities Checklist (ABC) was "designed to assess behavioral problems in adults within institutional settings." Wheeler, p. 142. Subsequently, the original ABC was revised for patients not institutionalized, specifically for FXS (ibid., same section). Clinicians, physicians, and researchers use the Behavioral Abnormalities Checklist-FXS-Specific (ABC-FXS) scale to access specific behaviors in FXS patients. The ABC-FXS scale has six subscales, including (i) irritability, (ii) hyperactivity, (iii) responsiveness / lethargy, (iv) social avoidance, (v) stereotypic behavior, and (vi) inappropriate speech. The ABC-FXS scale, like the ADAMS, is a 4-point Likert scale ranging from 0 (no problem) to 3 (severe problem). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Wheeler A, Raspa M, Bann C, Bishop E, Hassl D, Sacco H, Bailey DB.2014. “Anxiety attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome” Am J Med Genet Part A 164A:141–155, 141 [Overview of the project]

[0010] This disclosure relates to a method for treating one or more behavioral symptoms of Fragile X syndrome in a subject. The method comprises administering an effective dose of cannabidiol (CBD) transdermally to a subject, thereby treating one or more behavioral symptoms of Fragile X syndrome in the subject.

[0011] In some embodiments, the CBD is (-)-CBD. The effective dose of CBD may be approximately 50 mg to 500 mg per day. In some embodiments, the effective dose of CBD is started at approximately 50 mg per day and gradually increased to approximately 500 mg per day. The effective dose of CBD can be started at approximately 50 mg per day and gradually increased to approximately 250 mg per day.

[0012] In some embodiments, the effective dose of CBD is started at 250 mg per day. The effective dose of CBD can be started at 500 mg per day. In some embodiments, a dose of 500 mg per day is administered to patients weighing more than 35 kg. CBD can be administered in a once-daily dose or in two divided doses per day. In some embodiments, the effective dose of CBD may be 390 mg per day in divided doses.

[0013] CBD can be formulated as a gel or oil. In some embodiments, CBD is formulated as a permeation-enhancing gel. The gel can contain 1% (wt / wt) to 7.5% (wt / wt) CBD. In some embodiments, the gel contains 4.2% (wt / wt) CBD. In some embodiments, the gel contains 7.5% (wt / wt) CBD.

[0014] In some embodiments, the transdermal formulation may be a cream, ointment, or patch. CBD can be delivered by bandage, pad, or patch.

[0015] Alleviation of one or more behavioral symptoms of Fragile X syndrome may include improvement in the overall score of the Anxiety, Depression, and Mood Scale (ADAMS). In some embodiments, alleviation of one or more behavioral symptoms of the FXS may include improvement in one or more subscales of the ADAMS. Alleviation of one or more behavioral symptoms of Fragile X syndrome may include improvement in one or more scales of the ABC-FXS (Abnormal Behavior Checklist for Fragile X).

[0016] In some embodiments, one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, irritability, lethargy, stereotypic behavior, and inappropriate speech. The behavioral symptoms to be alleviated may be any one of the following: generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, irritability, lethargy, stereotypic behavior, inappropriate speech, emotional functioning, psychosocial health, written communication, socialization, play and leisure, coping skills, internalizing behavior, externalizing behavior, tantrums / emotional instability, hyperactivity / impulsivity, quality of life, or any combination thereof. In some embodiments, a single symptom is alleviated. In some embodiments, two, three, four, five, six, seven, eight, or nine symptoms are alleviated.

[0017] CBD can be administered transdermally to the upper arm and shoulder of the subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject.

[0018] CBD can be synthetic CBD. CBD can be refined CBD. CBD can be plant-derived.

[0019] Transdermal administration of an effective dose of cannabidiol (CBD) can reduce the severity of at least one adverse event or side effect compared to oral administration of CBD. At least one adverse event or side effect may be a gastrointestinal (GI) adverse event.

[0020] At least one adverse event or side effect may be liver function. In some embodiments, at least one adverse event is somnolence. In some embodiments, the frequency and intensity of somnolence are reduced as an adverse event.

[0021] In another embodiment, a method is provided for treating one or more behavioral symptoms of autism spectrum disorder (ASD) in a subject by transdermal administration of an effective amount of CBD to the subject, wherein one or more behavioral symptoms of ASD are treated in the subject.

[0022] Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior in approximately 1 million children and adolescents aged 5 to 17 years in the United States. Autism spectrum disorder refers to a range of conditions characterized by impairments in social communication, including anxiety, repetitive patterns of behavior, and impairments in verbal and non-verbal communication, as well as difficulties in the development and maintenance of relationships. Autism can be diagnosed at any age, but because symptoms generally appear within the first two years of life, it is referred to as a "developmental disorder." Research suggests that genes may interact with environmental influences to affect development and cause ASD. More recent research suggests that ASD is associated with disruption of the endogenous cannabinoid system.

[0023] ASD is a behavioral diagnosis with a range of symptoms generally characterized by impairments in the ability to communicate and engage in social interactions with others.

[0024] One or more behavioral symptoms of treatable ASD include, for example, social avoidance, general anxiety, hyperactivity, depressive mood, and obsessive-compulsive behavior. Alleviation of one or more behavioral symptoms of ASD can include improvement in the total score of the Anxiety-Depression-Mood Scale (ADAMS). In some embodiments, alleviating one or more behavioral symptoms of ASD can include improvement in one or more sub-scales of ADAMS.

[0025] In some embodiments, CBD is (-)-CBD. The effective amount of CBD can be from about 50 mg to about 500 mg per day. In some embodiments, the effective amount of CBD starts at about 50 mg per day and is incrementally increased to about 500 mg per day. The effective amount of CBD can start at about 5mg per day and be incrementally increased to about 250 mg per day.

[0026] In some embodiments, the effective amount of CBD starts at 250 mg per day. The effective amount of CBD can start at 500 mg per day. In some embodiments, a dose of 500 mg per day is administered to patients weighing over 35 kg. CBD can be administered in a once-daily dose or in divided doses twice a day. In some embodiments, the effective amount of CBD can be 390 mg in divided daily doses.

[0027] CBD can be formulated as a gel or an oil. In some embodiments, CBD is formulated as a penetration-enhancing gel. The gel can contain from 1% (wt / wt) CBD to 7.5% (wt / wt) CBD. In some embodiments, the gel contains 4.2% (wt / wt) CBD. In some embodiments, the gel contains 7.5% (wt / wt) CBD.

[0028] In some embodiments, the transdermal formulation can be a cream, a plaster, or an ointment. CBD can be delivered by a bandage, a pad, or a patch.

[0029] Alleviation of one or more behavioral symptoms of ASD can include improvement in the total score of the Anxiety-Depression-Mood Scale (ADAMS). In some embodiments, alleviation of one or more behavioral symptoms of ASD can include improvement in one or more subscales of ADAMS.

[0030] In some embodiments, one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior. The behavioral symptoms that are alleviated can be any one or any combination of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior. In some embodiments, a single symptom is alleviated. In some embodiments, two, three, or four behavioral symptoms are alleviated.

[0031] CBD can be administered transdermally to the upper arm and shoulder of the subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject.

[0032] CBD can be synthetic CBD. CBD can be refined CBD. CBD can be plant-derived.

[0033] Transdermal administration of an effective dose of cannabidiol (CBD) can reduce the severity of at least one adverse event or side effect compared to oral administration of CBD. At least one adverse event or side effect may be a gastrointestinal (GI) adverse event. At least one adverse event or side effect may be a liver function adverse event. In some embodiments, at least one adverse event is somnolence. In some embodiments, the frequency and severity of somnolence are reduced as an adverse event.

[0034] In another embodiment, a method is provided for treating or alleviating one or more symptoms of moderate to severe autism spectrum disorder in a subject. The method comprises administering an effective amount of cannabidiol (CBD) to the subject to treat one or more symptoms of moderate to severe autism spectrum disorder. In some embodiments, the one or more symptoms include generalized anxiety, clinical anxiety, irritability, inappropriate speech, stereotypes, social withdrawal, repetitive behaviors, and hyperactivity.

[0035] In some embodiments, CBD is administered as an add-on therapy.

[0036] In some embodiments, the subject is also administered one or more psychotropic drugs. In some embodiments, the one or more psychotropic drugs are selected from the group consisting of antidepressants, anxiolytics, psychostimulants, antipsychotics, and combinations thereof.

[0037] In some embodiments, one or more psychotropic agents include antipsychotics. In some embodiments, the antipsychotics are selected from risperidone, haloperidol, olanzapine, and quetiapine fumarate.

[0038] In some embodiments, one or more psychotropic agents include psychostimulants. For example, the psychostimulant can be selected from the group consisting of clonidine, guanfacine, methylphenidate hydrochloride, atomoxetine hydrochloride, dexamfetamine, and lisdexamfetamine mesylate.

[0039] In some embodiments, patients experience significant improvement in stereotypes, repetitive behaviors, or both. In addition to or instead of this, in some embodiments, patients experience significant improvement in irritability, communication deficits, or both.

[0040] In some embodiments, CBD is administered transdermally.

[0041] In some embodiments, all treatment-related adverse events are mild and transient.

[0042] In some embodiments, the effective dose is 250 mg, 500 mg, or 750 mg of CBD per day. In some embodiments, the effective dose is 250 mg or 500 mg of CBD per day. In some embodiments, the effective dose is administered in two divided doses per day.

[0043] In some embodiments, CBD is administered in a pharmaceutically acceptable formulation that does not contain THC. In some embodiments, CBD is administered without THC or other cannabis extracts. In some embodiments, CBD is synthetic CBD. In some embodiments, CBD is an extract. In some embodiments, CBD is a purified product.

[0044] CBD can be administered transdermally to the upper arm and shoulder of the subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject.

[0045] CBD can be synthetic CBD. CBD can be refined CBD. CBD can be plant-derived.

[0046] CBD can be formulated as a gel or oil. In some embodiments, CBD is formulated as a permeation-enhancing gel. The gel can contain 1% (wt / wt) to 7.5% (wt / wt) CBD. In some embodiments, the gel contains 4.2% (wt / wt) CBD. In some embodiments, the gel contains 7.5% (wt / wt) CBD.

[0047] In some embodiments, the transdermal formulation may be a cream, ointment, or patch. CBD can be delivered by bandage, pad, or patch. [Modes for carrying out the invention]

[0048] As used herein, the terms “to treat” or “treatment” mean reducing, improving, mitigating or alleviating at least one symptom (such as a behavioral symptom) of a condition, disease, or disorder in a subject such as a human, or improving a verifiable measure related to the condition, disease, or disorder.

[0049] As used herein, the term “clinical efficacy” refers to the ability to produce the desired effect in humans as demonstrated by clinical trials conducted by the U.S. Food and Drug Administration (FDA) or an equivalent institution in another country.

[0050] As used herein, the terms “cannabidiol” or “CBD” refer to cannabidiol; cannabidiol prodrugs; and pharmaceutically acceptable derivatives of cannabidiol, including pharmaceutically acceptable salts of cannabidiol, cannabidiol prodrugs, and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and its pharmaceutically acceptable salts, solvates, metabolites (e.g., cutaneous metabolites) and metabolic precursors. The 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), which are incorporated herein by reference.

[0051] As used herein, the term “administer transdermally” means bringing CBD into contact with the skin of a patient or subject under conditions that are effective for CBD to penetrate the skin.

[0052] Fragile X syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning problems, and various physical characteristics. FXS affects approximately 1 in 4,000 males and 1 in 8,000 females. Individuals with FXS may exhibit one or more characteristics of ASD (Autism Spectrum Disorder).

[0053] This disclosure relates to a method for treating one or more behavioral symptoms of Fragile X syndrome in a subject by transdermal administration of an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of Fragile X syndrome are treated in the subject.

[0054] The disclosure also relates to a method for treating one or more behavioral symptoms of autism spectrum disorder (ASD) in a subject by transdermal administration of an effective amount of cannabidiol (CBD) to the subject, wherein one or more behavioral symptoms of ASD are treated in the subject.

[0055] Clinical and preclinical data support the potential of CBD in the treatment of epilepsy, arthritis, cancer, and fragile X syndrome. Therapeutic drugs utilizing innovative transdermal technologies that enable sustained and controlled delivery of treatment-level CBD are being developed. 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. By bypassing first-pass metabolism in the liver, transdermal delivery potentially allows for lower dose levels of the active ingredient while increasing bioavailability and improving the safety profile. Transdermal delivery also bypasses the gastrointestinal tract, reducing GI-related adverse events and the potential for CBD to be broken down by stomach acid into THC, which can be associated with undesirable psychoactive effects. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of somnolence, an adverse event commonly associated with oral administration of CBD. Transdermal delivery of CBD can also avoid liver function adverse events commonly associated with oral administration of CBD. In some embodiments, transdermal administration of an effective dose of CBD reduces the severity of at least one adverse event by approximately 15% to approximately 95% compared to oral administration of CBD.

[0056] CBD may be in gel form and can be pharmaceutically manufactured as a clear, permeability-enhancing gel designed to provide controlled drug delivery with once or twice daily transdermal administration. CBD gels may contain 1% (wt / wt) to 7.5% (wt / wt) CBD. For example, a CBD gel may have 4.2% (wt / wt) or 7.5% (wt / wt) CBD. CBD gels can be applied topically by the patient or caregiver to the patient's upper arm and shoulder, back, thigh, or any combination thereof.

[0057] The CBD gel may contain a diluent and a carrier, as well as other conventional excipients, such as wetting agents, preservatives, and suspension / dispersing agents.

[0058] CBD gel may contain 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 with 1 to 6 carbon atoms present in an amount of about 15% to about 95% (wt / wt) of the composition; c. a first permeation enhancer present in an amount of about 0.1% to about 20% (wt / wt) of the composition; and d. water in an amount necessary to bring the composition to a total of 100% (wt / wt). Other formulations of CBD gel can be found in International Publication No. 2010 / 127033, the full contents of which are incorporated herein by reference. [Examples]

[0059] [Example 1] Study design and data A total of 20 patients (mean age = 10.8, SD = 4.0) participated in the 12-week trial. Eighteen fragile X patients (14 males, 4 females) aged 6 to 17 years (mean = 11.2, SD = 3.96), confirmed by molecular documentation of complete FMR1 mutations, completed the open-label FAB-C trial up to week 12. CBD gel was administered in addition to other medications. The first six weeks of the trial were designed to escalate the patient's dose. The dose was started at 50 mg CBD per day and could be increased up to 250 mg CBD per day. Weeks 7-12 of the trial included a maintenance period, during which patients were treated with the maximum dose of 250 mg CBD per day established by week 6. At completion of the trial, patients were eligible to participate in an open-label extension trial for up to 12 months.

[0060] The primary endpoint of this clinical trial was the change in the combined score of the Anxiety, Depression and Mood Scale (ADAMS) from baseline to week 12. The ADAMS is a 28-item scale designed to assess generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, and depressed mood. It has been validated in patients with FXS.

[0061] The results for the primary endpoint are summarized in Table 1, and the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12 for the ADAMS overall score are described in detail.

[0062] [Table 1]

[0063] Table 2 summarizes the subscales of ADAMS and details the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12.

[0064] [Table 2]

[0065] Compared to baseline overall scores, patients treated with CBD transdermal gel showed a 44% reduction in ADAMS overall scores (p<0.0001). Furthermore, patients treated with CBD transdermal gel showed statistically and clinically significant improvements compared to baseline in all but one of the ADAMS subscales (i.e., manic / hyperactive behavior, social avoidance, generalized anxiety, and obsessive-compulsive behavior) at week 12. No significant changes were observed in the depressive mood subscale of ADAMS.

[0066] Multiple secondary efficacy endpoints include the Abnormal Behavior Checklist-FXS (ABC-FXS), the Child Anxiety Rating Scale (PARS-R), the Visual Academic System (VAS) for Anxiety, Hyperactivity, and Tantrums / Emotional Instability, Vineland Adaptive Behavior (VLD) III, and the Child's Quality of Life (PedsQL(TM)). Both the PARS-R and the Vineland scales are assessed by clinicians, while the other scales are assessed by caregivers.

[0067] Primary and secondary endpoints were evaluated before drug administration and at 12 weeks post-administration. The results for secondary endpoints reinforced the findings demonstrated in ADAMS. Consistent with the findings from ADAMS, patients administered CBD transdermal gel showed statistically and clinically significant reductions at week 12 in all subscales of the ABC-FXS (i.e., irritability, hyperactivity, social responsiveness / lethargy, social avoidance, stereotypic behavior, and inappropriate speech) and in the overall scores of both the PARS-R (i.e., items 5 and 7).

[0068] Patients also showed significant improvement between baseline and week 12 scores on all PedsQL subscales except for some VLD subscales (e.g., communication, daily living skills), as well as some VLD subscales. Both VLD and ADAMS were administered during the second extension phase of the trial.

[0069] The results of the ABC-FXS are summarized in Table 3, and the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12 are detailed.

[0070] [Table 3]

[0071] The results of the PARS-R are summarized in Table 4, and the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12 are detailed.

[0072] [Table 4]

[0073] Table 5 summarizes the VAS results for anxiety, hyperactivity, and tantrums / emotional instability.

[0074] [Table 5]

[0075] The results from PedsQL are summarized in Table 6, detailing the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12.

[0076] [Table 6]

[0077] The results of VLD III are summarized in Table 7, and the mean (standard deviation) values ​​of the effectiveness scale at baseline and week 12 are detailed.

[0078] [Table 7]

[0079] Among the 18 patients who completed the 12-week treatment, the mean improvement in generalized anxiety and depression (ADAMS overall score) reached 44% (p<0.01), with particular benefits observed in generalized anxiety (51%; p<0.01) and obsessive-compulsive behavior subscales (48%; p<0.05). Furthermore, ABC FXS Measurements showed improvements in abnormal behavior ranging from 28% (hyperactivity subscale; p0<.05) to 60% (stereotypic subscale; p0<.01), while social avoidance (p<0.01) and interpersonal responsiveness / lethargy subscales (p<0.01) improved by 55% during the treatment period. Beyond individual symptoms, quality of life improved by 17% (p=0.01).

[0080] The trial met its primary endpoint without issue, achieving a 44% improvement in the ADAMS overall score at week 12 compared to baseline (P<0.0001). The trial also achieved clinically meaningful improvements in all ABC-FXS measures toward key symptoms of FXS, including irritability, hyperactivity, interpersonal responsiveness, social avoidance, stereotypic behavior, and inappropriate speech.

[0081] After a 12-week open-label trial, patients were invited to participate in a one-year open-label extension trial. 72% (n=13) of the 18 patients who completed the initial 12-week trial participated in the extension trial. The open-label extension trial is ongoing, but some data has been collected up to week 38 (12 weeks of the initial trial and up to 6 months of the extension trial). The results of the extension trial are based on two collected measures (ADAMS and ABC). FXS The study demonstrates sustained gains in these areas. In fact, subjects who completed their 38-week visit (n=4) showed a significant improvement from screening in generalized anxiety and depression, with participants experiencing a mean improvement of 74% on the ADAMS overall score. Similar improvements were observed in abnormal behavior, ranging from 75% (irritability subscale) to 96% (social avoidance subscale) and 97% (interpersonal responsiveness / lethargy subscale) at 38 weeks.

[0082] An open-label extension trial is underway, and data have been collected up to week 51. The results are shown in Table 8 (ABC). FXS This is summarized in the table (ADAMS).

[0083] [Table 8]

[0084] [Table 9]

[0085] The CBD gel exhibited excellent skin tolerability and was well-tolerated. One patient discontinued treatment due to exacerbation of a pre-existing eczema. No other adverse events led to discontinuation, and none were considered serious. The most common adverse events were mild to moderate gastroenteritis (n=6) and upper respiratory tract infection (n=5). However, no patients experienced drug-related GI events during the 12-week treatment period, and no THC was detected in plasma.

[0086] The clinical results of the trial are important for many FXS patients worldwide who currently lack approved treatment options to manage their symptoms. Improvements in anxiety, social avoidance, and irritability data, as measured by ADAMS, ABC-FXS, and PARS-R, are particularly significant. The CBD gel was very well tolerated in children and adolescents with FXS.

[0087] [Example 2] Monographs of patients reported by their parents The following is a report from a caregiver regarding a 7-year-old child who participated in the above trial and is continuing the extended trial. The caregiver's son has fully mutant fragile X syndrome. Prior to the trial, the child was reported to have a very severe GI problem, being nonverbal, having a severe intellectual disability, significantly reduced vision, still requiring diapers, and needing to be fed via a feeding tube every two hours. Before the start of the trial, the child had never made eye contact, could hardly leave home without excessive emotional distress, never initiated any form of communication, and had an extreme aversion to being touched, including by his parents, to the point that even family members could not sit next to him, and he would leave the room if anyone entered.

[0088] Within the first two weeks of the trial, patients began making more eye contact, initiating physical contact with family members, and initiating emotional contact with family members, such as holding their mother's hand and trying to stay in the same room as them. They also showed improved ability to go out to the point where their families were able to take their very first vacation together.

[0089] After the initial trial ended and several weeks into the extension trial, caregivers recorded another significant change in the patient. The patient began greeting family members, starting and participating in more complex games, showing / sharing preferences for things instead of simply rejecting everything, and showing interest in the family pets. The patient also allowed doctors to touch and hug them without becoming upset. The patient began using gesture signs (sign language) for the first time in their life. For the first time in their life, the patient communicated very clearly that they missed their mother and longed to be hugged and held by their mother.

[0090] Patients have reported being happier, more relaxed, able to engage with the world in ways they couldn't before, and able to learn new skills they couldn't before. Their teachers, therapists, and assistants have also noted these changes.

[0091] [Example 3] Treatment for ASD 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 (4 to 17 years old) consisted mainly of individuals with moderate to severe ASD. To measure and evaluate the safety and efficacy of ZYN002 in the treatment of ASD-related behaviors using various efficacy assessments, ASD was confirmed according to the diagnostic and statistical manual for mental disorders, 5th edition (DSM-5). Various efficacy assessments included the Abnormal Behavior Checklist-Community (ABC-C); the Diagnostic and Observational Schedule for Autism (ADOS-2); and the Parent Rating Anxiety Scale-Autism Spectrum Disorder (PRAS-ASD). ZYN002 was administered as an add-on therapy to standard treatment to patients with moderate to severe ASD symptoms.

[0092] <Patient Demographics> The majority of patients were male (92%), with a mean age of 9.2 years. Patient weight 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, measured by comparative scores on ADOS(R)-2 (94%) and severity according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (92%). The mean ABC-C irritability score was 30.3, and nine patients (24.3%) had PRAS-ASD scores indicating potential clinical anxiety, further highlighting the severity of symptoms in the participating patient population.

[0093] The majority of patients (92%) participated in the clinical trial using at least one basic medication. 65% of patients were taking at least one psychotropic drug, such as an antidepressant, anxiolytic, or antipsychotic. Of the 37 subjects, 14 were taking antipsychotics: 11 were taking risperidone, 1 haloperidol, 1 olanzapine, and 1 quetiapine fumarate. 16 were taking psychostimulants or nootropics used for ADHD, such as clonidine (6), guanfacine (5), methylphenidate hydrochloride (7), atomoxetine hydrochloride (2), dexamfetamine (1), and lisdexamfetamine mesylate (2).

[0094] <Clinical Trial Protocol> Participants received CBD in the form of ZYN002 CBD transdermal gel at a total dose of 250 or 500 mg per day, twice daily for 14 weeks. After completing the 14-week course of treatment, participants could participate in a 6-month extension study. This trial evaluated multiple efficacy metrics, including ABC-C, PRAS-ASD, Autism Parenting Stress Index, Autism Impact Scale (AIM), and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-1). The ABC-C Irritability Subscale was used as the basis for approval of two atypical antipsychotics indicated for ASD.

[0095] <Result> All five subscales of the ABC-C and the Parent Appraisal Anxiety Scale-Autism Spectrum Disorder (PRAS-ASD) showed both statistically significant and clinically meaningful improvements compared to baseline over 14 weeks of treatment. Table 10 summarizes the ABC-C results at weeks 6 and 14.

[0096] Table 10 summarizes the improvements at week 14 for each subscale of A, B, C, and C. All results were statistically significant, with p<0.001 for all subscales.

[0097] [Table 10]

[0098] In children with this severity of ASD who were also receiving antipsychotic medication, a 40% improvement in stereotyped behaviors on the ABC scale, a 33% improvement in repetitive behaviors on the Parent-Rated Anxiety Scale, and an unexpected overall improvement were observed. The results were statistically significant and clinically meaningful.

[0099] Other efficacy evaluation results support the findings demonstrated in ABC-C. For example, patients treated with ZYN002 experienced a mean improvement of 46% from a baseline score of 40.8 at week 14, as measured by PRAS-ASD (p<0.001), and 57% of patients were rated as significantly or greatly improved at week 14, as measured by Clinical Global Impression-Improvement (CGI-I).

[0100] The adverse event (AE) profile was consistent with the 12-week results of the Vulnerable X trial (FAB-C). ZYN002 was well-tolerated in this trial, and no serious adverse events (SAEs) were reported. 28 patients completed the 14-week trial, a discontinuation rate consistent with other trials of ASD. Only one patient dropped out of follow-up, and post-treatment efficacy was not evaluated. Less than half of the patients (49%) experienced some adverse event (unrelated to or related to the study drug), all of which were mild (75%) or moderate (25%). Only 14% of patients experienced adverse events considered to be treatment-related, all of which were application site-related and mostly mild and transient. No serious adverse events were reported during this trial. Eighteen patients who completed the BRIGHT trial participated in an open-label extension study.

[0101] While irritability, communication deficits, and some repetitive movements are core autistic behaviors, the reduction in their scales was particularly remarkable. The magnitude of the effects on hyperactivity and stereotypic behaviors was especially significant because these are among the behaviors most difficult to improve with treatment interventions.

Claims

1. A method for treating one or more symptoms of moderate to severe autism spectrum disorder in a subject, Administer an effective amount of cannabidiol (CBD) to the subject. A method comprising, for treating one or more of the aforementioned symptoms of moderate to severe autism spectrum disorder.

2. The method according to claim 1, wherein one or more of the symptoms include generalized anxiety, clinical anxiety, irritability, inappropriate speech, stereotypes, social withdrawal, repetitive behaviors, and hyperactivity.

3. The method according to any one of claims 1 to 2, wherein the CBD is administered as an add-on therapy.

4. The method according to claim 3, wherein the subject is also administered one or more psychotropic drugs.

5. The method according to claim 4, wherein the one or more psychotropic drugs include at least one drug selected from the group consisting of antidepressants, anxiolytics, psychostimulants, antipsychotics, and combinations thereof.

6. The method according to claim 4 or 5, wherein the one or more psychotropic drugs include an antipsychotic drug.

7. The method according to claim 6, wherein the antipsychotic drug is selected from the group consisting of risperidone, haloperidol, olanzapine, and quetiapine fumarate.

8. The method according to claim 4 or 5, wherein the one or more psychotropic agents include a psychostimulant.

9. The method according to claim 8, wherein the psychostimulant is selected from the group consisting of clonidine, guanfacine, methylphenidate hydrochloride, atomoxetine hydrochloride, dexamfetamine, and lisdexamfetamine mesylate.

10. The method according to any one of claims 1 to 9, wherein the patient experiences a significant improvement in stereotyped behavior, repetitive behavior, or both.

11. The method according to any one of claims 1 to 10, wherein the patient experiences a significant improvement in irritability, communication deficit, or both.

12. The method according to any one of claims 1 to 11, wherein the CBD is administered transdermally.

13. The method according to any one of claims 1 to 12, wherein all treatment-related adverse events are mild and transient.

14. The method according to any one of claims 1 to 13, wherein the effective amount of CBD is 250 mg, 500 mg, or 750 mg in total per day.

15. The method according to any one of claims 1 to 14, wherein the effective amount of CBD is 250 mg or 500 mg in total per day.

16. The method according to any one of claims 1 to 15, wherein the effective amount is administered in two divided doses per day.

17. The method according to any one of claims 1 to 16, wherein the CBD is administered in a pharmaceutically acceptable formulation that does not contain THC.

18. The method according to any one of claims 1 to 17, wherein the CBD is synthetic CBD.

19. The method according to any one of claims 1 to 17, wherein the CBD is purified CBD.

20. The method according to any one of claims 1 to 17, wherein the CBD is plant-derived CBD.

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