Methods for treating a subject having a disorder on the autism spectrum

Abstract

A method of treating autism spectrum disorder is provided. The method includes administering to a human subject in need thereof a compound having the structure of Formula (I): or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This invention relates to a method for treating autism spectrum disorder (ASD) by administering a therapeutically effective amount of a FAAH inhibitor to a subject in need. Background Technology

[0002] Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by core symptoms of social communication deficits, as well as the presence of repetitive and restrictive behaviors and interests. ASD affects approximately 1 in 132 people worldwide, with detailed epidemiological data in the United States indicating an even higher rate, affecting 1 in 36 children. The higher severity of ASD core symptoms, lower behavioral and adaptive abilities, and coexisting physical and mental health conditions have been shown to negatively impact the quality of life (QoL) of individuals with ASD. Interventions that can affect ASD symptoms have the potential to improve the QoL and daily functioning of individuals with autism.

[0003] Interventions capable of influencing ASD symptoms have the potential to improve QoL and daily functioning in individuals with autism. However, despite decades of research focused on the development of therapeutics, no drugs targeting the core symptoms of ASD have been approved. Aripiprazole and risperidone are approved for use in ASD, specifically for the treatment of irritability, defined as mood instability, physical aggression, self-injurious behavior, and temper tantrums or breakdowns. However, a significant unmet need remains for effective pharmacological therapies targeting the biological mechanisms or key biochemical pathways underlying the core symptoms of ASD. Summary of the Invention

[0004] An exemplary embodiment of the present invention is a method for treating autism spectrum disorder (ASD) in a human subject. The method includes administering, specifically orally, a therapeutically effective amount of a compound having the structure of formula (I) to the subject.

[0005] (I)

[0006] Or a pharmaceutically acceptable salt thereof. In some examples, the compound may be administered as a free base or a dihydrochloride. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily.

[0007] Administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof may: prevent or reduce autistic social impairment in a subject; improve at least one of the subject's social cognition, social communication, and social interaction; reduce the subject's repetitive behaviors; and / or alleviate the subject's anxiety. Repetitive behaviors may be selected from the group consisting of stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, and identity behaviors.

[0008] Administration can increase plasma concentrations of endogenous fatty acid amides (FAAs) by at least 100%. FAAs can be arachidonic acid ethanolamine (AEA), oleoyl ethanolamine (OEA), and / or palmitoyl ethanolamine (PEA). Administration can increase plasma concentrations of endogenous AEA by at least 400%. Administration can increase plasma concentrations of endogenous OEA by at least 300%. Administration can increase plasma concentrations of endogenous PEA by at least 400%.

[0009] In another aspect of this application, a method for treating autistic social impairment in human subjects is provided. The method includes administering, specifically orally, a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some examples, the compound may be administered as a free base or a dihydrochloride salt. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily. Following administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, at least one of the subject's social cognition, social communication, and social interaction is improved.

[0010] In another aspect of this application, a method for reducing repetitive behaviors in human subjects suffering from ASD is provided. Repetitive behaviors may be selected from the group consisting of stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, and homosexual behaviors. The method comprises administering, specifically orally, a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some examples, the compound may be administered as a free base or a dihydrochloride salt. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily.

[0011] In another aspect of this application, a method for treating anxiety in a human subject suffering from ASD is provided. The method comprises administering, specifically orally, a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some examples, the compound may be administered as a free base or a dihydrochloride salt. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily.

[0012] In another aspect of this application, a method is provided for treating one or more core symptoms of autism in a human subject suffering from ASD. Core symptoms of autism may include deficits in social communication and / or repetitive and restrictive behaviors and interests. The method comprises administering, specifically orally, a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some examples, the compound may be administered as a free base or a dihydrochloride salt. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily.

[0013] In another example, a method for treating autism spectrum disorder (ASD) in a human subject is provided. The method includes: obtaining eye-tracking data corresponding to the subject's gaze patterns and attention; and analyzing the eye-tracking data using a machine learning module trained to distinguish subjects with ASD from those with typical development to determine whether the subject is likely to have ASD. When the machine learning module identifies the subject as likely to have ASD, a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject, specifically orally. In some examples, the compound may be administered as a free base or a dihydrochloride. In one example, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day, specifically at a dose of 25 mg twice daily.

[0014] These and other aspects of the invention will become apparent to those skilled in the art after reading the following detailed description of the invention (including the accompanying drawings and claims). Attached Figure Description

[0015] Figure 1A The following clinical trial, based on Example I, illustrates the change over time of ABI-CD scores in the placebo group and the JNJ-42165279 BID group relative to baseline mean LS (±SE), as determined by MMRM analysis.

[0016] Figure 1B The following example I shows the mean (±SE) of ABI-CD scores over time relative to baseline in the placebo group and the JNJ-42165279 BID group in a clinical trial according to Example I.

[0017] Figure 1C The following clinical trial, based on Example I, illustrates the change over time in the ABI-SC score relative to baseline mean LS (±SE) in the placebo group and the JNJ-42165279 BID group, as determined by MMRM analysis.

[0018] Figure 1D The changes in ABI-RB scores over time relative to baseline mean (±SE) in the placebo group and the JNJ-42165279 BID group, as determined by MMRM analysis, are shown separately in the clinical trial according to Example I below.

[0019] Figure 2A The following example I shows the mean (±SE) of the total SRS-2 T score over time relative to baseline in the placebo group and the JNJ-42165279 BID group in a clinical trial according to Example I.

[0020] Figure 2B The following clinical trial, based on Example I, illustrates the change over time in the SRS-2 total T score relative to baseline as mean LS (±SE) in the placebo group and the JNJ-42165279 BID group, as determined by MMRM analysis.

[0021] Figure 3A The mean plasma concentrations (±SE) of AEA in the placebo group and the JNJ-42165279 BID group are shown in the clinical trial according to Example I below.

[0022] Figure 3B The mean plasma concentrations (±SE) of PEA in the placebo group and the JNJ-42165279 BID group are shown in the clinical trial according to Example I below.

[0023] Figure 3C The mean plasma concentrations (±SE) of OEA in the placebo group and the JNJ-42165279 BID group are shown in the clinical trial according to Example I below.

[0024] Figure 4A The following Example II illustrates the effect size (Cohen's d) of the change in total SRS-2 score at week 12 from baseline in selected ASD patients treated with JNJ-42165279 and in participants treated with placebo, for patients selected by ADOS-2 and ADOS-2+ trained ML (XGB, LR, RF or SVM).

[0025] Figure 4B The following Example II illustrates the change in total SRS-2 score at week 12 compared to baseline in selected ASD patients treated with JNJ-42165279 and in participants treated with placebo, for patients with ADOS-2 and ADOS-2+ trained ML (XGB, LR, RF or SVM) driven patients. Detailed Implementation

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings set forth in this specification. All patents, published patent applications, and publications referenced herein are incorporated herein by reference as if fully set forth herein. It should be noted that, unless the context clearly determines otherwise, the singular forms “a,” “an,” “the,” and “described” as used herein and in the appended claims include plural references.

[0027] Unless otherwise stated, the term "at least" preceding a series of elements should be understood to refer to each element in the series. Those skilled in the art will recognize, or can determine, various equivalents of the specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered by this invention.

[0028] Throughout this specification and the following claims, unless the context otherwise requires, the word “comprising” and variations such as “including” and “containing” shall be understood to imply inclusion of the stated integers or steps or groups of integers or steps, but not to exclude any other integers or steps or groups of integers or steps. When used herein, the term “comprising” may be replaced by the terms “containing” or “including”, or sometimes by the term “having”.

[0029] When used herein, “consisting of” excludes any element, step, or component not specified in the elements of the claim. When used herein, “consisting substantially of” does not exclude material or steps that do not substantially affect the essential and novel features of the claim. Any of the foregoing terms “comprising,” “containing,” “including,” and “having” may be replaced by the terms “consisting of” or “substantially of” to change the scope of this disclosure whenever used herein in the context of an aspect or embodiment of this patent application.

[0030] As used herein, the connecting term "and / or" between multiple listed elements is understood to include both individual options and combined options. For example, in the case where two elements are connected by "and / or", the first option means applying the first element in the absence of the second element. The second option means applying the second element in the absence of the first element. The third option means applying both the first and second elements together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0031] Unless otherwise indicated, any numerical value, such as the concentration or concentration range described herein, is to be understood to be modified by the term “about” in all cases. Therefore, numerical values ​​generally include ±10% of the stated value. For example, a concentration of 1 ng / mL includes 0.9 ng / mL to 1.1 ng / mL. Similarly, a concentration range of 1 ng / mL to 10 ng / mL includes 0.9 ng / mL to 11 ng / mL. More specifically, numerical values ​​may include ±1%, ±3%, or ±5% of the stated value. Unless the context clearly indicates otherwise, as used herein, numerical ranges explicitly include all possible subranges, all individual numerical values ​​within such ranges, including integers and fractions within such ranges.

[0032] As used herein, the terms "subject" or "patient" refer to an animal, and preferably a mammal. According to a particular embodiment, the subject is a mammal, including non-primates (e.g., camels, donkeys, zebras, cows, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, marmosets, or mice) or primates (e.g., monkeys, chimpanzees, or humans). In a particular embodiment, the subject is a human. In a particular embodiment, the subject is a female human. In other embodiments, the subject is a male human.

[0033] As used herein, the term "treatment" is intended to refer to an improvement or reversal of at least one measurable physical parameter associated with a disease or disorder as described herein, which is not necessarily identifiable in the subject, but is identifiable in the subject. The term "treatment" may also refer to remission, prevention of progression, or at least delay of the progression of a disease or disorder. In one particular embodiment, "treatment" means reducing, preventing the development or onset of, or shortening the duration of one or more symptoms associated with a disease or disorder as described herein. In one particular embodiment, "treatment" means preventing the recurrence of a disease or disorder. In one particular embodiment, "treatment" means an improvement in the survival rate of a subject with a disease or disorder. In one particular embodiment, "treatment" means the elimination of a subject's disease or disorder.

[0034] As used herein, the term “therapeutic effective amount” refers to the amount of an active compound or agent in an tissue system, animal, or human that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician, including the relief of one or more symptoms of the disease or disorder being treated; and / or the reduction of the severity of one or more symptoms of the disease or disorder being treated.

[0035] As used herein, the term "inhibitor" refers to a compound that reduces, prevents, inactivates, desensitizes, or downregulates FAAH expression or activity. The active agent can be used in the methods of this invention to treat or prevent medical diseases or disorders mediated by inhibition or modulation of FAAH, such as those described herein.

[0036] As used herein, the term “baseline” refers to samples or data (e.g., biofluids, assays, scores, measurements or other assessments) obtained from a subject prior to the administration of the intervention, specifically prior to the initiation of administration of the FAAH inhibitor to the subject.

[0037] The endocannabinoid system is believed to play a crucial role in the regulation of the immune system, pain perception, emotion, motivation, mood, fear, and anxiety responses. Unlike classical neurotransmitters, which are synthesized and stored in neurons until release, arachidonic acid ethanolamine (AEA) is produced on demand from selected membrane phospholipids and released from cells. In the nervous system, AEA is produced after postsynaptic activation and can act as a retrograde inhibitor of neuronal activity via its binding to the presynaptic CB1 receptor. After being reuptaken by cells, AEA and other fatty acid amides (FAAs) are rapidly inactivated by enzymatic hydrolysis. The primary scavenging enzyme for arachidonic acid ethanolamine is fatty acid amide hydrolase (FAAH), which is expressed in various tissues and is highly expressed in the brain. Therefore, administration of FAAH inhibitors to modulate the endocannabinoid system can modulate core symptoms associated with social communication deficits, as well as restrictive and repetitive behaviors associated with ASD.

[0038] This application relates to a method for treating ASD by administering a therapeutically effective amount of a FAAH inhibitor to subjects in need. This enzyme is primarily responsible for degrading various fatty acid amides (FAAs), including the endocannabinoids N-arachidonicylethanolamine or arachidonic acid ethanolamine (AEA), palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA). Therefore, FAAH inhibitors reduce or slow the catabolic metabolism of FAAs (including AEA, PEA, and / or EOA), resulting in elevated endogenous levels (e.g., plasma concentrations) of AEA, PEA, and / or EOA in subjects treated with FAAH inhibitors.

[0039] Specifically, the FAAH inhibitor administered to the subject in the method of this application can be a compound having the structure of formula (I):

[0040] Formula (I)

[0041] Or a pharmaceutically acceptable salt thereof. The compound of formula (I) is also known as 4-(2,2-difluoro-benzo[1,3]dioxane-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide or JNJ-42165279. This compound is a potent, selective, and orally bioavailable FAAH inhibitor. It is a substrate of the FAAH enzyme and inhibits its activity by covalently binding to the catalytic site of the FAAH enzyme. Enzyme activity is restored by slowly hydrolyzing the covalently bound drug fragment from the active site and regenerating the enzyme activity FAAH. Specifically, the compound of formula (I) can be administered as a free base or as a pharmaceutically acceptable salt thereof.

[0042] The term "pharmaceutically acceptable salt" refers to a salt of any of the compounds described herein that is known to be non-toxic and commonly used in pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the bioavailability of the compound described herein and is not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of compounds include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as, for example, inorganic acids, such as hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar acids; or organic acids, such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, para-aminosalicylic acid, dihydroxynaphthyl acid, and similar acids. Conversely, the salt form can be converted to a free base form by treatment with a suitable base. Furthermore, when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts may include organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, etc., salts with organic bases (e.g., primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinine ring, pyridine, quinoline and isoquinoline); benzylamine, N-methyl-D-glucosamine, hebamin salts, and salts with amino acids (such as, for example, arginine, lysine, etc.). Conversely, this salt form can be converted to a free acid form by acid treatment.

[0043] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0044] In some embodiments, the FAAH inhibitor is the hydrochloride salt of 4-(2,2-difluoro-benzo[1,3]dioxacyclopenten-5-ylmethyl)-piperazin-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide. Specifically, the hydrochloride salt is the following dihydrochloride salt:

[0045]

[0046] 4-(2,2-Difluoro-benzo[1,3]dioxacyclopenten-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide dihydrochloride

[0047] It should be noted that, unless the context clearly specifies otherwise, references to FAAH inhibitors, specifically to compounds of formula (I) discussed further below, include their pharmaceutically acceptable salts.

[0048] Because inhibition of FAAH enzymes reduces or slows the catabolism of FAAs and thus increases the plasma concentration of endogenous FAAs in the subject, in another embodiment, the method of this application includes administering a FAAH inhibitor to the subject at a therapeutically effective dose to maintain the plasma concentration of endogenous FAAs (such as AEA, OEA, and / or PEA) at or above an elevated level. For example, a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof may be administered to the subject at a dose to maintain an elevated plasma concentration of endogenous AEA at or above 5.0 nmol / L after an initial treatment period. The initial treatment period may be an initial period of administration of the FAAH inhibitor until the concentration of endogenous FAAs (AEA, OEA, and / or PEA) reaches a steady state. The initial treatment period may not exceed 3 days, 5 days, 7 days, 10 days, 14 days, or 15 days.

[0049] In one particular implementation, a FAAH inhibitor may be administered to a subject at a dosage regimen that maintains an endogenous AEA plasma concentration at or above 5.0 nmol / L after an initial treatment period of 15 days. In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that maintains an elevated plasma concentration of endogenous OEA at or above 20.0 nmol / L or at or above 25.0 nmol / L after an initial treatment period as defined above. More specifically, a FAAH inhibitor may be administered to a subject at a dosage regimen that maintains an endogenous OEA plasma concentration at or above 20.0 nmol / L or at or above 25.0 nmol / L after an initial treatment period of 15 days. In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that maintains an elevated plasma concentration of endogenous PEA at or above 15.0 nmol / L or 17.0 nmol / L after an initial treatment period as defined above. More specifically, FAAH inhibitors can be administered to subjects at a dose regimen that maintains plasma concentrations of endogenous PEA at or above 15.0 nmol / L or at or above 17.0 nmol / L after an initial 15-day treatment period.

[0050] In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous FAA levels by at least 100%, about 100% to about 550%, about 110% to about 500%, or about 125% to about 450% compared to baseline after an initial treatment period. The initial treatment period may be the initial period of administration of the FAAH inhibitor until the concentration of endogenous FAA (AEA, OEA, and / or PEA) reaches a steady state. The initial treatment period may not exceed 3 days, 5 days, 7 days, 10 days, 14 days, or 15 days. In one example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous FAA levels by at least 100%, about 100% to about 550%, about 110% to about 500%, or about 125% to about 450% compared to baseline after a 15-day initial treatment period.

[0051] In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous AEA by at least 100%, at least 200%, at least 300%, at least 400%, about 225% to about 550%, about 375% to about 550%, about 225% to about 400%, about 400% to about 550%, or about 350% to about 450% compared to baseline after the initial treatment period as defined above. The initial treatment period may not exceed 3 days, 5 days, 7 days, 10 days, 14 days, or 15 days. In one example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous FAA by at least 100%, at least 200%, at least 300%, at least 400%, about 225% to about 550%, about 375% to about 550%, about 225% to about 400%, about 400% to about 550%, or about 350% to about 450% compared to baseline after a 15-day initial treatment period.

[0052] In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous OEA by at least 100%, at least 200%, at least 300%, about 200% to about 450%, about 225% to about 350%, about 350% to about 425%, about 225% to about 425%, or about 275% to about 350% compared to baseline after an initial treatment period as defined above. The initial treatment period may not exceed 3 days, 5 days, 7 days, 10 days, 14 days, or 15 days. In one example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous FAA by at least 100%, at least 200%, at least 300%, about 200% to about 450%, about 225% to about 350%, about 350% to about 425%, about 225% to about 425%, or about 275% to about 350% compared to baseline after a 15-day initial treatment period.

[0053] In another example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous PEA by at least 100%, about 100% to about 175%, about 110% to about 160%, about 100% to about 150%, about 140% to about 160%, about 100% to about 140%, or about 110% to about 130% compared to baseline after an initial treatment period as defined above. The initial treatment period may not exceed 3 days, 5 days, 7 days, 10 days, 14 days, or 15 days. In one example, a FAAH inhibitor may be administered to a subject at a dosage regimen that increases the plasma concentration of endogenous FAA by at least 100%, about 100% to about 175%, about 110% to about 160%, about 100% to about 150%, about 140% to about 160%, about 100% to about 140%, or about 110% to about 130% compared to baseline after a 15-day initial treatment period.

[0054] In some examples, the plasma concentration of the aforementioned FAAs (e.g., AEA, OEA, PEA) can be determined as the mean steady-state plasma concentration, the pre-dose concentration after the initial treatment period (i.e., before the subject receives his / her daily dose of the FAAH inhibitor), or the post-dose concentration after the initial treatment period (i.e., immediately after the subject receives his / her daily dose of the FAAH inhibitor).

[0055] FAAH inhibitors can be administered to subjects via any suitable route of administration, preferably orally, at a dose of about 25 mg / day to 50 mg / day. FAAH inhibitors can be administered once, twice, or three times daily. FAAH inhibitors can be administered daily for a period of at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In one exemplary embodiment, the FAAH inhibitor is administered orally at a dose of 25 mg to 50 mg daily for a period of at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. In another example, the FAAH inhibitor can be administered orally at a dose of 25 mg twice daily. More specifically, the FAAH inhibitor can be administered orally at a dose of 25 mg twice daily for a period of at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. All amounts mentioned in this paragraph refer to the free form (i.e., free base or free base equivalent, non-salt or non-solvent form). The dosages described above are presented as the free equivalent, i.e., the amount that would be administered as if in free form. If salt is used, the mass of the salt form needs to be calculated from the molecular weight ratio between the salt and the free form. The daily doses mentioned above are calculated based on an average body weight of approximately 70 kg and should be recalculated in pediatric applications or when used on subjects with significantly different body weights.

[0056] In one aspect of this application, a pharmaceutical composition is provided comprising a therapeutically effective amount of a FAAH inhibitor, specifically 4-(2,2-difluoro-benzo[1,3]dioxane-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. As used herein, the term "pharmaceuticalally acceptable excipient" refers to a non-toxic, biologically tolerable, or in other words, biologically suitable for administration to a subject, such as an inert substance, which is added to a pharmacological composition or, in other words, used as a medium, carrier, or diluent to facilitate the administration of the pharmaceutical agent and is compatible with the pharmaceutical agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0057] Pharmaceutical compositions comprising FAAH inhibitors, specifically 4-(2,2-difluoro-benzo[1,3]dioxacyclopenten-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide or a pharmaceutically acceptable salt thereof, may be administered via any suitable route of administration, such as oral, parenteral (including subcutaneous (sc), intramuscular (im), and intravenous (iv)), rectal, transdermal, buccal, or nasal. FAAH inhibitors may also be administered directly to the nervous system via routes including but not limited to intracranial, intraspinal, intraventricular, intrathecal, intrasheath, intracisternal, intraspinal, and / or perispinal routes via intracranial or spinal needles and / or catheters with or without pump devices. Preferably, FAAH inhibitors are administered orally. Compositions suitable for oral administration include powders, granules, aggregates, tablets, compressed or coated pellets, hard or gelatin capsules, syrups, emulsions, and suspensions. Suitable compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions. In a preferred embodiment, the FAAH inhibitor is administered orally, such as via tablets, gelatin capsules, or orally ingested liquids.

[0058] Oral tablets may include FAAH inhibitors, specifically 4-(2,2-difluoro-benzo[1,3]dioxane-5-ylmethyl)-piperazine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide or a pharmaceutically acceptable salt thereof, mixed with pharmaceutically acceptable excipients such as inert fillers, diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, colorants, flow aids, and / or preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, lactose monohydrate, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, hydroxypropyl methylcellulose, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinylpyrrolidone, sodium glycolate starch, microcrystalline cellulose, cross-linked polyvinyl N-pyrrolidone or PVP, and alginate are suitable disintegrants. Binders may include hydroxypropyl methylcellulose (HPMC), starch, and gelatin. Lubricants (if present) may be magnesium stearate, stearic acid, or talc. Gliders (if present) may be silica (SiO2), such as colloidal silica. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0059] Capsules for oral administration can include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, FAAH inhibitors can be mixed with solid, semi-solid, or liquid diluents. Soft gelatin capsules can be prepared by mixing FAAH inhibitors with water, oils (such as peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0060] Orally administered liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dried product for reconstitution with water or other suitable media immediately before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, such as oils (e.g., almond oil or graded coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and (if desired) flavoring agents or coloring agents.

[0061] In one aspect of this application, a method for treating ASD in a human subject, specifically an adult or adolescent, is provided. The method comprises administering (e.g., orally, such as a tablet) to the subject a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. Administration of a therapeutically effective amount of a FAAH inhibitor reduces the severity and / or burden of ASD in the subject.

[0062] The severity of ASD in human subjects can be quantified using any appropriate test or scale for assessing the severity of ASD in human subjects. For example, the severity of ASD in human subjects can be assessed using the Caregiver Overall Severity Impression (Caregiver GI-S) scale. The Caregiver GI-S is a single-item tool that asks caregivers to rate their overall impression of the severity of ASD symptoms in children under their care. The scale ranges from 1 (none) to 7 (severe), with higher scores indicating more severe symptoms.

[0063] The burden of ASD in human subjects can be quantified using any suitable test or scale for assessing the burden of ASD in human subjects. For example, the burden of ASD in human subjects can be assessed using the Zarit Burden Interview (ZBI), specifically the short version of the ZBI scale. The short version of the ZBI is a 22-item scale designed to assess the psychological burden experienced by caregivers. Items ask caregivers how they feel and react, ranging from 0 to 4 (nearly always). The ZBI overall score is the sum of all item scores and can range from 0 to 88, where a higher score indicates a higher burden. A negative change in the ZBI overall score indicates improvement. The ZBI overall score can also be categorized into the following burden categories: almost no burden or no burden (0–20), mild to moderate burden (21–40), moderate to severe burden (41–60), and severe burden (61–88).

[0064] In one example, a method for reducing the severity or burden of ASD in a human subject is provided. The method involves administering (e.g., orally, such as a tablet) a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. For example, a reduction in ASD severity can be quantified using the caregiver GI-S as described above. A reduction in ASD burden can be quantified using the ZBI, specifically a shortened version of the ZBI discussed above.

[0065] In another aspect of this application, a method for treating ASD (or treating core symptoms and / or related symptoms of ASD) is provided, the method comprising administering to a subject a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. Administering a therapeutically effective amount of a FAAH inhibitor reduces the severity of one or more core symptoms or related symptoms of ASD. Core symptoms or related symptoms can be those of ASD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. For example, core symptoms may include deficits in social communication and the presence of repetitive and restrictive behaviors and interests. In another example, related symptoms may include one or more of the following: deficits in self-regulation, irritability, anxiety, depression, attention problems, and challenging behaviors, such as aggressive behavior. In yet another example, core symptoms or related symptoms may include one or more of the following: deficits in social communication, restrictive behaviors, mood and anxiety, challenging behaviors, and deficits in self-regulation.

[0066] Core or related symptoms of ASD, such as deficits in social communication, restrictive behaviors, mood and anxiety, challenging behaviors, and self-regulation deficits, can be quantified using any suitable test or scale. For example, core or related symptoms of ASD can be measured using the Janssen Autism Knowledge Engine (JAKE), which includes a JAKE task group with biosensors and a reporting tool that includes the Autism Behaviors Checklist (ABI) scale (available at https: / / www.janssenscience.com / therapeutic-areas / neuroscience / clinical-research-tools / abi, which is incorporated herein by reference). The ABI is a 62-item caregiver report scale developed by Janssen Research and Development. The ABI assesses core and related symptoms of ASD and has five domains: Social Communication (SC), Restrictive Behaviors (RB), Mood and Anxiety, Self-Regulation, and Challenging Behaviors. Each ABI item answers one of two possible dimensions: quality (the extent to which a person performs a particular behavior) or frequency (how often a particular behavior occurs). Each item is rated on a scale of 0-3 (from less than very often [frequency] or not at all to no help [quality]).

[0067] There are three versions of the ABI: the ABI or the full ABI, the ABI Short Form (ABI-S), and the ABI Clinician Interview (ABI-C). ABI-S is a shorter version of the ABI with approximately 20 items (available at https: / / www.janssenscience.com / therapeutic-areas / neuroscience / clinical-research-tools / abi-s, which is incorporated herein by reference). ABI-S includes the core domains and also covers five ASD domains: (a) social communication, (b) restrictive behaviors, (c) mood and anxiety, (d) self-regulation, and (e) challenging behaviors. In the study of Example I (discussed below), the caregiver scale was completed using ABI-S at weeks 2 (center), 6 (home), and 10 (home). ABI-C covers the domains and subdomains of ABI-S and is intended to be appropriately completed by clinicians after interviewing caregivers and after observing or interviewing individuals with ASD. Clinicians are required to rate the severity or level of impairment of observed or described behaviors on a scale of 1 to 7, where 1 indicates no behavioral impairment and 7 indicates severe difficulty in a functional area. Each of the five domains has 14 items. For all ABI domains, the rating ranges from 0 to 3 (ABI-S) or 1 to 7 (ABI-C), where a higher score indicates more severe ASD symptoms, and a decrease (negative change) relative to baseline represents improvement.

[0068] In one example, the core symptoms and / or related symptoms of ASD can be quantified using the ABI, ABI-S, or ABI-C. In another example, each of the core symptoms or related symptoms of ASD can be quantified using any suitable test or scale. In one example, each of the core symptoms or related symptoms of ASD (such as the following symptoms: social communication deficits, restrictive behaviors, mood and anxiety, self-regulation deficits, and challenging behaviors) can be quantified using the corresponding ASD domain of the ABI, ABI-S, or ABI-C.

[0069] In one example, core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include social impairment, repetitive behaviors, and / or anxiety. Specifically, core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include social impairment, repetitive behaviors, and anxiety. In another example, core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include social impairment, repetitive behaviors, anxiety, and / or challenging behaviors. Specifically, core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include social impairment, repetitive behaviors, anxiety, restrictive behaviors, challenging behaviors, and / or deficits in self-regulation. Specifically, core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include social impairment, repetitive behaviors, anxiety, restrictive behaviors, challenging behaviors, and deficits in self-regulation. In another example, the core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor are challenging behaviors. In yet another example, the core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include restrictive behaviors, challenging behaviors, and / or deficits in self-regulation. Specifically, the core or related symptoms of ASD that are alleviated by administering a therapeutically effective dose of a FAAH inhibitor may include restrictive behaviors, challenging behaviors, and deficits in self-regulation.

[0070] Limiting behaviors may include insisting on doing things the same way, focusing on certain topics or activities and being unable to shift attention, having strange mannerisms or unusual movements of his / her hands or fingers, performing repetitive actions, behaving in ways that could lead to self-harm, and / or overreacting to noise, sound, or touch. Challenging behaviors may include multiple items such as physical aggression towards others, exhibiting aggressive reactions when he / she is frustrated or stressed, and / or having emotional outbursts or tantrums. Impaired self-regulation may include acting without thinking, rapidly switching from one topic or behavior to another, and / or hyperactivity.

[0071] Social impairment in ASD can include persistent deficits in social communication and / or social interaction. For example, social impairment can include deficits in social-emotional reciprocity, deficits in nonverbal communication behaviors, and / or deficits in developing, maintaining, and understanding relationships. In another example, social impairment can include one or more symptoms selected from groups consisting of: social awareness, social cognition, social communication, social motivation, and restricted interests and repetitive behaviors, such as those described in the Social Response Scale 2 (SRS-2), discussed further below. In another example, social impairment can include one or more symptoms selected from groups consisting of: social awareness, social cognition, social communication, and social motivation, such as those described in SRS-2. In yet another example, social impairment can include one or more symptoms selected from groups consisting of: social awareness, social cognition, social communication, social motivation, and social communication and interaction, which are comprehensive subscales of social awareness, social cognition, social communication, and social motivation, all as described in SRS-2. Social impairment in ASD can be quantified using any suitable test or scale. For example, social impairment in ASD can be quantified using SRS-2.

[0072] The SRS-2 is a 65-item scale completed by caregivers that differentiates autism spectrum disorder from other childhood mental disorders by identifying the presence and extent of social impairment in autistic children. There are three versions of the SRS-2: one for preschool children, one for school-aged children, and one for adults. The PI uses the instructions in the SRS-2 manual to select the most appropriate version for each participant, either the school-aged or adult version. Each of the 65 items has four possible responses: “Not True,” “Sometimes True,” “Often True,” and “Almost Always True.” Each item is scored from 0 to 3 based on an appropriate rating worksheet. The SRS-2 also has five subscales: Social Awareness (Awr), Social Cognition (Cog), Social Communication (Com), Social Motivation (Mot), and Restricted Interests and Repetitive Behaviors (RRB). The sum of the subscales excluding the raw RRB score constitutes the raw Social Communication and Interaction (SCI) score. The raw scores for each subscale can be converted to T-scores using an appropriate form. For both the T-score for each subscale and the total T-score, higher scores indicate more severe symptoms. Negative changes in the T-score indicate improvement.

[0073] In one example, a method is provided for treating social impairment in a human subject with ASD or for treating social impairment in a human subject with autism. The method includes administering (e.g., orally, such as a tablet) a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject. Administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject may alleviate one or more symptoms selected from the group consisting of social awareness, social cognition, social communication, social motivation, and restricted interests and repetitive behaviors, such as those described in SRS-2. In another example, administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject may alleviate one or more symptoms selected from the group consisting of social awareness, social cognition, social communication, and social motivation, such as those described in SRS-2. In yet another example, administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject may alleviate symptoms associated with social cognition, social communication, and / or social communication and interaction, such as those described in SRS-2. In another example, administration to a subject of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof reduced symptoms associated with social cognition and social communication, such as those described in SRS-2. In yet another example, administration to a subject of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof reduced symptoms associated with social communication and interaction, as described above.

[0074] Repetitive behaviors in ASD refer to restricted, repetitive patterns of behavior, interests, or activities in human subjects with ASD. For example, repetitive behaviors in ASD may include stereotyped or repetitive motor actions, object or verbal use; identity fixation, rigid adherence to routines, or ritualistic patterns of behavior or verbal or nonverbal behavior; unusually highly restricted fixed interests in intensity or focus; and / or overreaction or underreaction to sensory input, or unusual interest in sensory aspects of the environment. In one example, repetitive behaviors may include one or more symptoms selected from groups consisting of stereotyped behaviors, self-injurious behaviors, compulsive behaviors, ritualistic behaviors, identity behaviors, and restricted behaviors, such as those described in the Repetitive Behaviors Scale Revised Version (RBS-R) scale, as discussed further below. Repetitive behaviors can be quantified using any suitable test or scale. For example, repetitive behaviors can be quantified using the RBS-R.

[0075] The Repetitive Behavior Standards of Repetitive Behaviors (RBS-R) is a 43-item reporting scale completed by caregivers to indicate the occurrence of repetitive behaviors and the degree of the problem, ranging from 0 (no behavior) to 3 (the behavior is a serious problem). There are six subscales: stereotyped behaviors, self-injurious behaviors, compulsive behaviors, ritualistic behaviors, identity behaviors, and restricted behaviors. To score the RBS-R, the items of each subscale are summed; therefore, the scale presents six subscales. The stereotyped behaviors subscale ranges from 0 to 18; the self-injurious behaviors subscale ranges from 0 to 24; the compulsive behaviors subscale ranges from 0 to 24; the ritualistic behaviors subscale ranges from 0 to 18; the identity behaviors subscale ranges from 0 to 33; and the restricted behaviors subscale ranges from 0 to 12. The overall score is also calculated as the sum of all 43 items, ranging from 0 to 129. For all subscales and the overall score, a higher score indicates a more severe problem. Negative changes in subscale and overall scores indicate improvement.

[0076] In one example, a method is provided for treating and / or reducing repetitive behaviors in a human subject with ASD. The method includes administering (e.g., orally, such as tablets) to the subject a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. Administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject can alleviate one or more symptoms of the repetitive behaviors. For example, administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject can alleviate one or more symptoms selected from the group consisting of stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, identity behaviors, and restricted behaviors, such as those described in the RBS-R scale. In another example, administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject can reduce stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, and / or identity behaviors, such as those described in the RBS-R scale. In another example, administering a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to a subject can reduce stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, and identity behaviors, such as those described in the RBS-R scale.

[0077] Individuals with ASD exhibit abnormalities in processing, perceiving, and expressing emotions. ASD is also associated with depression and anxiety. In one example, anxiety in ASD may correspond to symptoms of one or more of the following disorders: Attention Deficit Hyperactivity Disorder, Oppositional Defiance Disorder, Conduct Disorder, Generalized Anxiety Disorder, Social Phobia, Separation Anxiety Disorder, Disruptive Mood Disorder, Major Depressive Episode, Manic Episode, Dysthymia Disorder, Schizophrenia, Autism / Asperger's Disorder, Anorexia, Bulimia, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Specific Phobias, Panic Attacks, Motor Tics, Vocal Tics, and Substance Abuse. In another example, anxiety in ASD may correspond to symptoms of one or more of the following Group 1 disorders: Attention Deficit Hyperactivity Disorder, Oppositional Defiance Disorder, Conduct Disorder, Generalized Anxiety Disorder, Social Phobia, Separation Anxiety Disorder, Disruptive Mood Disorder, Major Depressive Episode, Manic Episode, Dysthymia Disorder, Schizophrenia, Autism / Asperger's Disorder, Anorexia, Bulimia. In another example, anxiety in ASD can correspond to symptoms of one or more disorders in Group 1 and one or more disorders in Group 2: obsessive-compulsive disorder, post-traumatic stress disorder, specific phobias, panic attacks, motor tics, vocal tics, and substance abuse. For example, anxiety in human subjects with ASD can be quantified using any suitable test or scale. For instance, anxiety in human subjects with ASD can be quantified using the Child and Adolescent Symptom Checklist-Anxiety Scale (CASI-Anx).

[0078] The CASI-Anx assessment, completed by caregivers, evaluates symptoms of the following disorders: Attention Deficit Hyperactivity Disorder, Oppositional Defiance Disorder, Conduct Disorder, Generalized Anxiety Disorder, Social Phobia, Separation Anxiety Disorder, Disruptive Mood Disorder, Major Depressive Episode, Manic Episode, Dysthymia Disorder, Schizophrenia, Autism / Asperger's Disorder, Anorexia, and Bulimia. It also includes one or two key symptoms for each of the following disorders: Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Specific Phobias, Panic Attacks, Motor Tics, Vocal Tics, and Substance Abuse. The CASI-Anx is a 21-item anxiety scale with responses ranging from 0 (never) to 3 (very often), where higher scores indicate more severe anxiety. The symptom severity score is the sum of the responses to each item. The symptom severity score ranges from 0 to 63, with higher scores indicating more severe anxiety. Negative changes in the symptom severity score indicate improvement.

[0079] In one example, a method for treating and / or alleviating anxiety in a human subject with ASD is provided. The method includes administering (e.g., orally, such as tablets) to the subject a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. Administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject may alleviate anxiety or one or more symptoms of anxiety in the human subject with ASD. Administering the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof to the subject may alleviate one or more symptoms of anxiety in the human subject with ASD, which are symptoms associated with a disorder selected from: attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, generalized anxiety disorder, social phobia, separation anxiety disorder, disruptive mood disorder, major depressive episode, manic episode, dysthymia disorder, schizophrenia, autism / Asperger's disorder, anorexia, bulimia, obsessive-compulsive disorder, post-traumatic stress disorder, specific phobias, panic attacks, motor tics, vocal tics, and substance abuse, such as those described in the CASI-Anx scale. In another example, administration to a subject of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof may reduce one or more symptoms of anxiety in a human subject with ADS, wherein the one or more symptoms are associated with a disorder selected from the following: Attention Deficit Hyperactivity Disorder, Oppositional Defiance Disorder, Conduct Disorder, Generalized Anxiety Disorder, Social Phobia, Separation Anxiety Disorder, Disruptive Mood Disorder, Major Depressive Episode, Manic Episode, Dysthymia Disorder, Schizophrenia, Autism / Asperger's Disorder, Anorexia, and Bulimia. In another example, administration to a subject of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof may reduce one or more symptoms of a Group 1 disorder and one or more symptoms of a Group 2 disorder in a human subject with ADS: Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Specific Phobias, Panic Attacks, Motor Tics, Vocal Tics, and Substance Abuse.

[0080] For all methods described herein, compounds having the structure of formula (I) or pharmaceutically acceptable salts thereof may be administered to human subjects identified as potentially having ASD based on biosensor data related to gaze patterns and attention collected from the subjects, specifically eye-tracking data corresponding to gaze patterns or attention. Eye-tracking data can be obtained using any suitable biosensors and tests to record eye movements in response to social and non-social stimuli from the subjects. The eye-tracking data can be analyzed using a machine learning module trained to distinguish subjects with ASD from those with typical development based on eye-tracking characteristics. The machine learning module analyzes the eye-tracking data to determine whether the subject is likely to have ASD. If the machine learning module determines that the subject is likely to have ASD, a therapeutically effective amount of a FAAH inhibitor is administered to the subject, specifically orally.

[0081] Example

[0082] The following embodiments are provided to further illustrate the essence of the present invention. It should be understood that the following embodiments do not limit the present invention, and the scope of the present invention is defined by the appended claims.

[0083] Example 1:

[0084] A clinical trial of 4-(2,2-difluoro-benzo[1,3]dioxacyclopenten-5-ylmethyl)-piperazin-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide (also known as JNJ-42165279) was conducted in human subjects with ASD. Example I was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, outpatient phase 2a study.

[0085] Eligible participants were aged 13–35 years, diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and confirmed using the Diagnostic Observational Scale for Autism Scale, Second Edition (ADOS-2) (score: ≥8). Participants must be healthy or medically stable, and on the age-bound BMI percentile growth chart, if age ≥18 years, their body mass index (BMI) must be between 18 and 35 kg / m². 2 Participants must be between the 5th and 95th percentiles, or, if under 18 years of age, between the 5th and 95th percentiles in body mass index. Participants must live with a parent or primary caregiver, or spend time with them weekly (at least 3 hours per day for at least 4 days, or on weekends). Additionally, any pharmacological, nutritional, or behavioral interventions for ASD must have begun at least one month prior to the baseline visit and remained consistent throughout the treatment period, or ended at least one month prior to the baseline visit. Participants must also have a composite score of at least 60 on the Kaufman Short Form Intelligence Test Version 2 (KBIT-2).

[0086] This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 2 study (NCT03664232). The study was designed to evaluate the efficacy and safety of JNJ 42165279 in adolescent and adult participants with ASD during a 12-week treatment period.

[0087] The study consisted of a 26-day screening period (day -26 to day -1), a 12-week double-blind treatment period (day 1 to day 85), and a 14-day (±1-week) follow-up period following the last dose of the study intervention (e.g., JNJ-42165279 or placebo). During treatment, eligible participants were randomized (1:1) to receive 25 mg JNJ-42165279 or a matched placebo twice daily (BID; 50 mg / day), once in the morning and once in the evening, with the doses spaced as close to 12 hours apart as possible. Randomization was stratified by sex and age (13–17 years and 18–35 years) to ensure balanced treatment allocation. The study intervention was administered at the research center during study visits (weeks 2, 4, 8, and 12) and self-administered at home by participants on all other days between visits.

[0088] This clinical study utilized the Janssen Autism Knowledge Engine (JAKE), which includes a JAKE task group with biosensors and a reporting tool that includes the Autism Scale (ABI). The ABI was used to assess the primary efficacy endpoint in Example I of the study. The primary efficacy endpoint included changes in ABI core domain (ABI-CD), ABI social communication (ABI-SC), and ABI repetitive / restrictive behaviors (ABI-RB) scores from baseline to day 85 (end of week 12). In addition to the primary ABI outcome, changes in ABI mood and anxiety, ABI challenging behaviors, ABI self-regulation, ABI clinician interview (ABI-C), and ABI short form (ABI-S) scores from baseline to day 85 (day 71 of ABI-S) were assessed as secondary outcomes.

[0089] The ABI-CD score is calculated by summing the scores of the ABI-SC and ABI-RB domains and dividing by the total number of items in those two domains. Each item in the domain is rated on a scale of 0-3 (from less than very often [frequency] or not at all to no help [quality]).

[0090] The ABI-SC domain score is calculated as the sum of the scores for the Social Communication domain divided by the total number of items in that domain.

[0091] Each item in the ABI-RB domain is rated on a scale of 0-3 (never less than very often). The ABI-RB domain score is calculated as the sum of the scores for the ABI-RB domains divided by the total number of items in that domain.

[0092] Other secondary efficacy endpoints included changes in ASD symptoms from baseline to day 85 using the Clinical Global Impression-Severity (CGI-S) scale, the Social Response Scale-2 (SRS-2) (as discussed above), the Abnormal Behavior Checklist (ABC) subscale, the Repetitive Behaviors Scale-Revised (RBS-R) scale (as discussed above), the Zarit Burden Interview (ZBI) short version scale (as discussed above), the Childhood and Adolescent Symptom Checklist-Anxiety (CASI-Anx) scale (as discussed above), and the Caregiver Global Impression of Severity (CGI-S) scale (as discussed above). Additionally, on day 85, improvements in ASD symptoms were assessed using the CGI-I scale, the Caregiver Treatment Assessment, and the Self-Global Impression of Improvement (Self-GI-I) scale (an adaptation of the CGI scale scored on day 85).

[0093] The CGI-S scale assesses the severity of all diseases. The CGI-S is a 7-point scale, ranging from 1 (normal, no disease) to 7 (most severe disease). It requires clinicians to assess the severity of participants' diseases, with higher scores indicating more severe diseases.

[0094] The ABC is a 58-item behavioral rating scale completed by caregivers and used to measure behavioral problems across five subscales: irritability, lethargy (social withdrawal), stereotyped behaviors, hyperactivity / disobedience, and inappropriate speech. Items are rated on a 4-point Likert scale (ranging from 0 [no problem] to 3 [severe problem]), with higher scores indicating more severe problems. To rate the ABC, the individual items of each subscale are simply summed to their respective totals. Therefore, the scale presents five subscale ratings. The irritability subscale ranges from 0 to 45; the lethargy / social withdrawal subscale from 0 to 48; the stereotyped behaviors subscale from 0 to 21; the hyperactivity / disobedience subscale from 0 to 48; and the inappropriate speech subscale from 0 to 12. Using all five subscales is inappropriate and should not be considered. For all ABC subscales, higher scores indicate more severe problems. Negative changes in ABC subscale ratings indicate improvement.

[0095] CGI-I is a single-item tool that requires clinicians to use a 7-point scale to assess the extent of improvement in participants from the start of treatment: 1 = significant improvement, 2 = substantial improvement, 3 = slight improvement, 4 = no change from baseline, 5 = slight worsening, 6 = substantial worsening, and 7 = significant worsening.

[0096] The caregiver treatment assessment is a questionnaire consisting of three items, completed at the end of the treatment period:

[0097] • The first question asked caregivers to rate their overall impression of the improvement in the autism of the child they were caring for since the start of the study medication. The seven answer options ranged from 1 "significant improvement" to 7 "significant worsening", with higher scores indicating more severe symptoms.

[0098] • The second question asks caregivers whether their nine specific symptoms have improved. The answer options are "yes" or "no".

[0099] • The third question asks caregivers about their interest in having the child under their care continue taking the investigational drug. There are five answer options, ranging from "not interested at all" to "extremely interested".

[0100] At the end of the treatment period, each participant was asked to use the single-item tool Self GI-I to give his / her impression of the overall improvement in ASD symptoms. The scale ranged from 1 (significant improvement) to 7 (significant worsening), with higher scores indicating more severe symptoms.

[0101] Safety was monitored throughout the study, including the incidence, severity, and type of treatment-adverse events (TEAEs), concomitant medications, clinical laboratory results, physical examinations (including weight, height, and BMI), vital signs, and electrocardiogram results. Suicidal ideation and suicidal behavior were also evaluated.

[0102] Blood samples were collected on days 1, 15, and 85, before and after administration, to determine JNJ-42165279 concentrations. Plasma JNJ-42165279 concentrations were determined using a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS / MS). Plasma concentration-time data for JNJ-42165279 were analyzed using population pharmacokinetic (PK) modeling.

[0103] To evaluate the relationship between plasma concentrations of FAAs (AEA, PEA, OEA) and efficacy. Venous blood samples were collected on days 1, 29, and 85 before and after administration to determine FAA concentrations.

[0104] The full analysis set (FAS) includes participants who received at least one dose of the study intervention at any dose level and had baseline and at least one post-baseline efficacy assessment. All efficacy analyses were performed on the FAS-BID analysis set, which consists of participants who received at least one BID dose of the study intervention and had baseline and at least one post-baseline efficacy assessment. All safety data were analyzed based on the safety analysis set, which consists of all participants who received at least one dose of the study intervention. The PK analysis set was defined as participants who received at least one dose of the study intervention and had at least one valid blood sample drawn for PK analysis.

[0105] The primary power outcome was analyzed using a mixed-effects model-repeated measures (MMRM). The model included the corresponding baseline scores of the instrument as covariates and included time, treatment, treatment duration, interaction, age group (13–17 years and 18–35 years, including extreme values), and sex as factors. An unstructured variance-covariance matrix was used.

[0106] Analysis of variance (ANOVA) models were used to assess caregiver perception of improvement in treatment assessments at the endpoint. For this purpose, treatment, age group (13–17 years, 18–35 years), and sex were included as factors. Values ​​and other secondary efficacy variables relative to baseline at each time point throughout the double-blind phase were descriptively summarized by treatment group. For secondary efficacy endpoints, comparisons between JNJ-42165279 and placebo were analyzed using the corresponding baseline scores of the instrument as covariates, as described for the primary efficacy analysis. On day 85 (day 71 for ABI-S), a nominal one-sided p-value <0.1 was considered an indicator of potential treatment effect.

[0107] TEAEs and serious TEAEs were coded using the Medical Dictionary of Regulatory Activities (MedDRA version 25.0) and summarized by system organ classification and preference criteria. Safety evaluations included assessments of laboratory tests, vital signs, ECG, and physical and neurological examinations, and TEAEs and serious TEAEs were summarized descriptively.

[0108] A correlation analysis was performed on the combination therapy group to examine the relationship between FAA plasma concentration and changes in efficacy assessment from baseline to endpoint. Efficacy assessment included all efficacy assessment scales and the total T score.

[0109] Of the 167 participants screened, 78 were randomized, with 63 of them randomized to BID (Best Injection). Of these, 15 participants (placebo: 7; JNJ-42165279: 8) received a once-daily (QD) dose (50 mg daily), and 62 participants received a BID dose (25 mg BID) (placebo: 30; JNJ-42165279: 32). One participant in the placebo BID group did not receive the study intervention, and one participant in the JNJ-42165279 BID group withdrew from the study after the baseline visit and did not complete the post-baseline assessment. Therefore, the FAS, FAS-BID, and safety analysis sets included 76, 62, and 77 participants, respectively.

[0110] Overall, 53 of the 62 (85.5%) treatment participants in the BID group completed the double-blind treatment phase, while 9 discontinued the study, with "other reasons" being the most common reason for discontinuation (n=4 [5.1%]). One participant in the JNJ-42165279 BID group withdrew from the study after the baseline visit and did not complete the post-baseline assessment. Discontinuation rates were comparable in both BID treatment groups (placebo: 4 [13.3%]; JNJ-42165279: 5 [15.6%]).

[0111] Table 1 below provides demographic information and baseline characteristics for the two BID groups in the clinical trial of Example 1.

[0112] Table 1.

[0113]

[0114] As shown in Table 1 above, demographic information and baseline characteristics were largely similar across groups. The majority of participants in the BID group were male (73.8%) and white (78.7%). 24 participants (39.3%) in the BID group were between 13 and 17 years of age. The placebo BID group showed a lower mean (SD) KBIT-2 composite score (92.5 [16.21]) than the JNJ-42165279 BID group (104.2 [28.90]). The mean (SD) ADOS-2 total score in the placebo BID group (16.4 [5.35]) was slightly higher than that in the JNJ-42165279 BID group (15.4 [5.30]).

[0115] Overall, 54 participants in the BID group (87.1%; placebo: 26, JNJ-42165279:28) had received at least one line of prior therapy. Within the BID group, 26 participants (41.9%) reported combined use of ASD therapies, with speech therapy (13%) and individual counseling or therapy (10%) being the most frequently used.

[0116] Table 2 presents the changes in ABI scores and domain scores from baseline to day 85 in the placebo and JNJ-42165279 BID groups, as determined by MMRM analysis. In the data presented in Table 2, negative changes in scores indicate improvement. P-values ​​(subtracting placebo) were determined based on an MMRM model, with treatment (placebo BID and JNJ-42165279 BID), visit duration, randomized age group (13–17 years, 18–35 years), sex, and the interaction between visit and treatment as factors, and baseline values ​​as covariates.

[0117] Table 2.

[0118]

[0119]

[0120]

[0121] Figure 1A The changes in ABI-CD scores over time relative to baseline (mean ± SE) for the placebo group and the JNJ-42165279 BID group are shown, and Figure 1B The mean (±SE) of ABI-CD scores over time relative to baseline is shown for the placebo and JNJ-42165279 BID groups of the same subjects as in Table 2 above. Based on MMRM analysis, at day 85, the least squares mean (LSM) difference ± standard error (SE) of ABI-CD scores between JNJ-42165279 and placebo (80% confidence interval [CI]; P value) indicated a non-significant improvement in ASD symptoms: -0.05 ± 0.09 (-0.17, 0.07; 0.284). The effect size of the change in ABI-CD scores from baseline to day 85 was 0.17.

[0122] Figure 1C and Figure 1D The changes in ABI-SC and ABI-RB scores over time relative to baseline mean (±SE) for the placebo group and the JNJ-42165279 BID group are shown, as determined by MMRM analysis of the same subjects as in Table 2 above. Figure 1C and Figure 1D Table 2 shows that the LSM difference ± SE (80% CI; P value) of ABI-SC score between JNJ-42165279 and placebo was -0.05 ± 0.10 (-0.18, 0.07; 0.290), and the ABI-RB score was -0.08 ± 0.10 (-0.21, 0.06; 0.231), with an effect size of 0.14 for both.

[0123] The primary endpoint (full ABI) did not reach the predefined statistical significance threshold. It should be noted that significant differences in baseline severity existed between treatments (as measured by ADOS-2, SRS-2, and ABI), with the placebo group exhibiting more severe symptoms. Even though baseline severity was included as a covariate in both the primary and secondary outcomes in the MMRM, baseline differences may impair the model's ability to detect treatment effects. Furthermore, the significantly lower baseline scores in the JNJ-42165279 group may have contributed to a floor effect on the ABI, thereby impairing the model's ability to detect changes in treatment.

[0124] Furthermore, the response anchors on the ABI were set to 1 and 0 to indicate the frequency of symptoms as "sometimes" or "never," respectively. The mean baseline ABI-CD score in the JNJ-42165279 group (1.07 ± 0.576) corresponded to the mean frequency of symptoms as "sometimes." Therefore, a decrease to 0 would indicate a frequency change to "never," which may be difficult to achieve with 12 weeks of pharmacological therapy. For the ABI, the minimum clinically significant difference and the sensitivity of effective treatment to changes have not been determined.

[0125] It should also be noted that the study in Example 1 was limited to a study population with mild to moderate baseline ASD symptoms. ADOS-2 was used to establish an ASD diagnosis for inclusion in the study, but study inclusion was not based on a symptom severity threshold.

[0126] Table 3 provides data generated from scales for secondary efficacy endpoints in the BID group of the study using Example I. In the data shown in Table 3, negative changes in scores indicate improvement. In the columns for evaluated domains / subscales, bold entries indicate those domains / subscales where scores indicate potential therapeutic effect. At day 85 (day 71 for ABI-S), a nominal one-sided p-value <0.1 was considered an indicator of potential therapeutic effect. Statistical testing was not controlled for test multiplicity of secondary endpoints.

[0127] For the data provided in Table 3, the ZBI scoring analysis was based on an analysis of covariance (ANCOVA) model, with treatment (placebo BID, JNJ-42165279 BID), age group (13–17 years, 18–35 years), and sex as factors, and baseline values ​​as covariates. The scoring analysis of treatment and self-GI-I caregiver assessments was based on an ANOVA model, with treatment (placebo BID, JNJ-42165279 BID), age group (13–17 years, 18–35 years), and sex as factors. All other scoring analyses in Table 3 were based on an MMRM model, with treatment (placebo BID, JNJ-42165279 BID), visitation, age group (13–17 years, 18–35 years), sex, and the interaction between visitation and treatment as factors, and baseline values ​​as covariates.

[0128] Table 3.

[0129]

[0130] The data provided in Table 3 indicate that, at the last time point (day 71), JNJ-42165279 BID showed greater reduction in ASD symptoms than the placebo group in 3 of the 6 domains of the ABI-S (ABI Short Form) (LSM difference ± SE [80% CI], P value: challenging behavior: -0.29 ± 0.13 [-0.45; -0.12]; RB: -0.23 ± 0.12 [-0.39; -0.07]; self-regulation: -0.43 ± 0.17 [-0.64; -0.21]) and in 1 of the 6 domains of the ABI-C (challenging behavior: -0.22 ± 0.16 [-0.42; -0.01]). In secondary outcomes such as social communication as measured by SRS-2 and repetitive behaviors and other related symptoms as measured by RBS-R, there were directional differences that favored JNJ-42165279 over placebo.

[0131] Of the secondary efficacy endpoints listed in Table 3, seven of the twelve rating scales indicated the potential therapeutic effect of JNJ-42164279 relative to placebo by day 85.

[0132] Figure 2A The mean (±SE) of the total SRS-2 T score over time relative to baseline is shown for the placebo group and the JNJ-42165279 BID group of the same subjects as in Table 3 above. Figure 2B The changes in the total SRS-2 T score over time relative to baseline (±SE) in the placebo group and the JNJ-42165279 BID group are shown, as determined by MMRM analysis of the same subjects as in Table 3 above. (See Table 3 and...) Figure 2A and Figure 2B As shown, on day 85, JNJ-42165279 showed a reduction in social impairment compared to placebo, as measured by the SRS-2 total score and three of the six subscale domains (social cognition, SC, SC, and interaction).

[0133] Notably, on the SRS-2 scale, the observed changes compared to placebo were directionally favorable to JNJ-42165279 treatment. The differences in ABI and SRS-2 outcomes observed in this study may be attributed to differences between the two scales. The SRS-2 is normalized using age-adjusted T-scores and has a greater number of SC items tailored to different age ranges (i.e., age-specific items). Furthermore, the SRS-2 scale data had fewer missing data points.

[0134] Table 3 also shows that JNJ-42165279 was associated with a greater reduction in repetitive behaviors, as measured by RBS-R for six of the seven specified outcomes (overall, stereotyped behaviors, self-harming behaviors, compulsive behaviors, ritualistic behaviors, and identity behaviors). Additionally, Table 3 shows that, compared to placebo, JNJ-42165279 also reduced anxiety (CASI-Anx score), caregiver perception of ASD severity (caregiver GI-S score), and caregiver rating of disease burden (ZBI score).

[0135] For subjects treated with BID, the mean (SD) duration of JNJ-42165279 treatment was 78.4 (19.33) days, ranging from 1 to 89 days, with a median duration of 85 days. Figure 3A The mean plasma concentrations (±SE) of AEA in the placebo group and the JNJ-42165279 BID group are shown. Figure 3B The mean plasma concentrations (±SE) of PEA in the placebo group and the JNJ-42165279 BID group are shown. Figure 3C The mean plasma concentrations (±SE) of OEA are shown in the placebo group and the JNJ-42165279 BID group. Figures 3A to 3C As shown, compared with placebo-treated participants, the mean concentrations of AEA, PEA, and OEA increased from baseline in participants treated with JNJ-42165279 and continued to rise throughout the treatment period. As these figures illustrate, JNJ-42165279 rapidly increased FAA levels (e.g., AEA, PEA, and / or OEA), with no further increases observed after two weeks. Furthermore, the peak and trough concentrations of each FAA were comparable between adults and adolescents treated with JNJ-42165279 (not shown).

[0136] The mean percentage change in plasma FAA concentration relative to baseline collected from adult and adolescent participants receiving either JNJ-42165279 or a placebo BID during the treatment period (i.e., days 15 and 85) is shown in Tables 4 and 5. Table 4 shows the mean percentage change in plasma fatty acid amide concentration relative to baseline collected from adult and adolescent participants receiving either JNJ-42165279 or a placebo BID prior to administration on days 15 and 85.

[0137] Table 4.

[0138]

[0139] a Average values ​​are presented for day 15 and day 85.

[0140] Table 5 shows the mean percentage change in plasma fatty acid amide concentration relative to baseline, collected from adult and adolescent participants receiving JNJ-42165279 or placebo BID 2.0 to 2.5 hours after administration on days 15 and 85.

[0141] Table 5.

[0142]

[0143] a Average values ​​are presented for day 15 and day 85.

[0144] In participants treated with JNJ-42165279, mean concentrations were significantly elevated before administration and between 2 and 2.5 hours after administration. In participants treated with placebo, mean FAA concentrations were observed to increase and decrease relative to baseline at various time points, with smaller changes compared to those observed in participants treated with JNJ-40411813.

[0145] Participants in the QD and BID treatment groups were divided into “high AEA” and “low AEA” groups to compare changes in SRS scores. Thresholds defining “high AEA” and “low AEA” in the JNJ-42165279 treatment group were determined based on the highest level observed in the placebo group (3.77 mol / L). Subjects with levels above 3.77 mol / L were identified as having “high AEA,” and those below 3.77 mol / L were identified as having “low AEA.” In the data shown in Table 6, negative changes in scores indicated improvement.

[0146] Table 6 provides the total SRS-2 T score (mean) from baseline to day 85 for the full analysis sets of low and high AEA levels, placebo group, and JNJ-42165279 group.

[0147] Table 6.

[0148]

[0149] The data provided in Table 6 show that in the “high AEA” group, participants with blood AEA levels above the threshold on day 85 exhibited the greatest reduction in total SRS scores. Participants in the “low AEA” group were similar to those in the placebo group.

[0150] In participants treated with JNJ-42165279, mean FAA concentrations increased from baseline and remained higher throughout the treatment period compared to participants treated with placebo. In the treatment group, participants with elevated AEA levels on day 85 showed greater reduction in total symptoms (SRS) compared to participants with similar AEA levels at baseline. At the endpoint, participants in the high AEA JNJ-42165279 group had the highest reduction in social impairment. The treatment effect was more significant in participants with elevated AEA levels in the JNJ-42165279 group. The observed effect may be related to the increased AEA concentrations during JNJ-42165279 treatment due to regulation of the endocannabinoid system.

[0151] Table 7 shows data on a list of treatment-term adverse events (TEAEs) experienced by at least 5% of patients in any treatment group for which a safety analysis set was provided.

[0152] Table 7.

[0153]

[0154]

[0155] The data in Table 7 show that, overall, 15 / 32 (46.9%) participants in the JNJ-42165279 group and 12 / 30 (40.0%) participants in the placebo group had at least one TEAE. Most reported TEAEs were assessed as unrelated to or suspected to be related to the study intervention and were of mild or moderate severity. The most common TEAEs (≥5% of participants in either treatment group; placebo vs. JNJ-42165279) were headache (2 [6.7%] vs. 1 [3.1%]) and elevated alanine aminotransferase (2 [6.7%] vs. 0). No deaths or severe TEAEs were reported. One participant in the placebo control group reported suicidal ideation, and it was not based on changes in the C-SSRS score. There were no clinically significant differences between the JNJ-42165279 and placebo groups in terms of laboratory values, vital signs, ECG, or physical / neurological examinations.

[0156] Overall, JNJ-42165279 demonstrated an acceptable safety profile in adolescents and adults with ASD, with no new safety signals identified. TEAEs were mild to moderate in severity. No changes in vital signs, routine safety tests, severe TEAES, or death were reported. Furthermore, no male fertility-related safety findings or TEAES were reported in this study.

[0157] Example II:

[0158] Eye-tracking (ET) features can be used to distinguish between ASD and idiosyncratic developmental disorder (TD) human subjects in the example, and can be used to detect gaze abnormalities in attention to social and non-social stimuli in human subjects with ASD. In Example II, a machine learning (ML) model was developed and trained to distinguish between ASD and TD using ET features. The trained ML model was used to analyze ET features obtained from human subjects participating in the clinical trial described above in Example I.

[0159] Baseline ET features related to gaze and focus during visual exploration, biomovement, activity monitoring, and social orientation tasks, obtained from two previous large-scale clinical trials, were used to develop and train ML models to differentiate ASD from TD using ET features that capture gaze patterns and attention. Age and gender distributions from the two training studies were matched to train the ML models.

[0160] The first of these training studies is an observational study (in which biomedical or health outcomes of participants identified as belonging to the study group are assessed) to evaluate the utility of JAKE in measuring the clinical symptoms of ASD in children and adults with ASD (NCT02668991). This first study includes three participant cohorts. For cohort 1 and cohort 2, there will be a 14-day screening phase extending from day 0 (baseline) to day 56 or day 70, respectively, and an 8-week (cohort 1) or 10-week (cohort 2) data collection phase. For cohort 3, the study will consist of screening visits and single-test visits, which may be combined.

[0161] The second training study was a multicenter, non-interventional study of TD children and adults. It consisted of two cohorts. Cohort 1 had 25 participants and a single administration of the JAKE task group, while Cohort 2 had two visits spaced 4 to 6 weeks apart, with two administrations of the JAKE task group at visits 1 and 2, resulting in a total of 75 assessments of the JAKE task group.

[0162] In Example II, four separate ML models (Extreme Gradient Boosting (XGB), Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM)) were trained using data from the aforementioned training study. Each trained ML model was evaluated using a repeated cross-validation process with hierarchical splits (5 folds, 10 repetitions). The features included in the inter-fold hierarchies were age, gender, and class distribution (ASD and TD).

[0163] After training the ML model, it was subsequently tested using an independent test dataset. The independent test dataset comprised baseline ET features obtained from human subjects participating in the clinical trial described above in Example 1, along with their ASD diagnoses confirmed using ADOS-2. The trained ML model was used to analyze the ET features from this independent test dataset. The trained ML model successfully predicted probable ASD patients using the independent test dataset. This demonstrates that ET features can be used to capture gaze abnormalities during attention to both social and non-social stimuli.

[0164] A bootstrap approach was performed by randomly sampling patients (initially included in Example I of the study using ADOS-2) to match the number of patients selected by the trained ML model, thus providing a fair assessment of efficacy. The performance results for each trained ML model are presented in Table 8 below: (1) trained XGB model, (2) trained LR model, (3) trained RF model, and (4) trained SVM model.

[0165] Table 8.

[0166]

[0167] The effect size (measured by Cohen's d) of the change in total SRS-2 score at week 12 compared to baseline was assessed among selected ASD patients using ADOS-2 and ADOS-2+ model-driven patient selection. Model-driven patient selection was based on the detection of probable ASD patients using any of the trained XGB model, trained LR model, trained RF model, and trained SVM model described above.

[0168] Figure 4A The effect size (Cohen's d) of the change in total SRS-2 score at week 12 compared to baseline is shown for selected ASD patients selected by ADOS-2 and ADOS-2+ trained ML (XGB, LR, RF or SVM) in participants treated with JNJ-42165279 and those treated with placebo. Figure 4A The stars shown represent all subjects in the modality. The squares shown represent the reduction in the number of subjects with ASD based on ML prediction. As in the ML method, the same N 100 randomizations were performed from the JNJ-42165279 treatment group and the placebo treatment group. The dashed boxes show the mean and standard deviation of those Cohen's d. Figure 4BThe changes in total SRS-2 score at week 12 compared to baseline were shown for selected ASD patients selected by ADOS-2 and ADOS-2+ trained ML (XGB, LR, RF, or SVM) in participants treated with JNJ-42165279 and those treated with placebo. Figure 4A and Figure 4B These results demonstrate that the ADOS-2+ML model-driven patient selection approach achieves a significant improvement in SRS-2 scores (approximately 0.3 more in Cohen's d) compared to ADOS-2-only patient selection.

[0169] The scope of the invention described herein and protected by the claims is not limited to the specific embodiments disclosed herein, as these embodiments are intended to illustrate several aspects of the invention. Any equivalent embodiments are intended to be within the scope of the invention. In fact, various modifications of the invention will become apparent to those skilled in the art from the foregoing description, in addition to those shown and described herein. Such modifications are also intended to fall within the scope of the appended claims. All publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A method for treating autism spectrum disorder (ASD) in a human subject, the method comprising: The subject was given a therapeutically effective amount of a compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salt.

2. The method according to claim 1, wherein a free base of the compound of formula (I) is applied.

3. The method according to claim 1, wherein the dihydrochloride salt of the compound of formula (I) is applied.

4. The method according to claim 1, wherein the compound is administered orally.

5. The method according to claim 4, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

6. The method according to claim 5, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

7. The method according to any one of claims 1 to 6, wherein the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof prevents or reduces the autistic social impairment of the subject.

8. The method of claim 7, wherein the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof improves at least one of the subject's social cognition, social communication, and social interaction.

9. The method according to any one of claims 1 to 6, wherein the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the repetitive behavior of the subject.

10. The method of claim 9, wherein the repetitive behavior is selected from the group consisting of stereotyped behavior, self-harming behavior, compulsive behavior, ritualistic behavior, and identity behavior.

11. The method according to any one of claims 1 to 6, wherein the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the anxiety of the subject.

12. The method according to any one of claims 1 to 6, wherein the administration increases the plasma concentration of endogenous fatty acid amides (FAA) by at least 100%.

13. The method of claim 12, wherein the FAA is arachidonic acid ethanolamine (AEA).

14. The method of claim 13, wherein the administration increases the plasma concentration of the endogenous level of AEA by at least 400%.

15. The method of claim 12, wherein the FAA is oleoylethanolamine (OEA).

16. The method of claim 15, wherein the administration increases the plasma concentration of the endogenous level of OEA by at least 300%.

17. The method of claim 12, wherein the FAA is palmitoylethanolamine (PEA).

18. A method for treating autistic social impairment in a human subject, the method comprising: The subject was given a therapeutically effective amount of a compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salt.

19. The method according to claim 18, wherein a free base of the compound of formula (I) is applied.

20. The method according to claim 18, wherein the dihydrochloride salt of the compound of formula (I) is applied.

21. The method of claim 18, wherein the compound is administered orally.

22. The method according to claim 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

23. The method according to claim 22, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

24. The method according to any one of claims 18 to 23, wherein, after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, at least one of the subject's social cognition, social communication, and social interaction is improved.

25. The method according to any one of claims 18 to 23, wherein the administration increases the plasma concentration of endogenous fatty acid amides (FAA) by at least 100%.

26. The method of claim 25, wherein the FAA is arachidonic acid ethanolamine (AEA).

27. The method of claim 26, wherein the administration increases the plasma concentration of the endogenous level of AEA by at least 400%.

28. The method of claim 25, wherein the FAA is palmitoylethanolamine (PEA).

29. A method for reducing repetitive behaviors in human subjects with autism spectrum disorder (ASD), the method comprising: The subject was given a therapeutically effective amount of a compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salt.

30. The method according to claim 29, wherein a free base of the compound of formula (I) is applied.

31. The method according to claim 29, wherein the dihydrochloride salt of the compound of formula (I) is applied.

32. The method of claim 29, wherein the compound is administered orally.

33. The method according to claim 32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

34. The method according to claim 33, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

35. The method according to any one of claims 29 to 34, wherein the repetitive behavior is selected from the group consisting of stereotyped behavior, self-harming behavior, compulsive behavior, ritualistic behavior, and identity behavior.

36. The method according to any one of claims 29 to 34, wherein the administration increases the plasma concentration of endogenous fatty acid amides (FAA) by at least 100%.

37. The method of claim 36, wherein the FAA is arachidonic acid ethanolamine (AEA).

38. The method of claim 37, wherein the administration increases the plasma concentration of the endogenous level of AEA by at least 400%.

39. A method for treating anxiety in a human subject with autism spectrum disorder (ASD), the method comprising: The subject was given a therapeutically effective amount of a compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salt.

40. The method according to claim 39, wherein a free base of the compound of formula (I) is applied.

41. The method according to claim 39, wherein the dihydrochloride salt of the compound of formula (I) is applied.

42. The method of claim 39, wherein the compound is administered orally.

43. The method according to claim 42, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

44. The method according to claim 43, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

45. The method according to any one of claims 39 to 44, wherein the administration increases the plasma concentration of endogenous fatty acid amides (FAA) by at least 100%.

46. ​​The method of claim 45, wherein the FAA is arachidonic acid ethanolamine (AEA).

47. The method of claim 46, wherein the administration increases the plasma concentration of the endogenous level of AEA by at least 400%.

48. The method of claim 45, wherein the FAA is oleoylethanolamine (OEA).

49. The method of claim 48, wherein the administration increases the plasma concentration of the endogenous level of OEA by at least 300%.

50. The method of claim 45, wherein the FAA is palmitoylethanolamine (PEA).

51. A method for treating one or more core symptoms of autism in a human subject with autism spectrum disorder (ASD), the method comprising: The subject was given a therapeutically effective amount of a compound having the structure of formula (I): (I) Or its pharmaceutically acceptable salt.

52. The method according to claim 51, wherein a free base of the compound of formula (I) is applied.

53. The method according to claim 51, wherein the dihydrochloride salt of the compound of formula (I) is applied.

54. The method of claim 51, wherein the compound is administered orally.

55. The method according to claim 54, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

56. The method of claim 55, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

57. The method according to any one of claims 51 to 56, wherein the core symptoms of autism include deficits in social communication.

58. The method according to any one of claims 51 to 56, wherein the core symptoms of autism include repetitive and restrictive behaviors and interests.

59. A method for treating autism spectrum disorder (ASD) in a human subject, the method comprising: Obtain eye-tracking data corresponding to the subject's gaze pattern and attention; The eye-tracking data was analyzed using a machine learning module trained to distinguish subjects with ASD from those with typical developmental characteristics in order to determine whether the subjects were likely to have ASD. When the machine learning module identifies the subject as potentially suffering from ASD, a therapeutically effective amount of a compound having the structure of formula (I) is administered to the subject. (I) Or its pharmaceutically acceptable salt.

60. The method according to claim 59, wherein a free base of the compound of formula (I) is applied.

61. The method according to claim 59, wherein the dihydrochloride salt of the compound of formula (I) is applied.

62. The method of claim 59, wherein the compound is administered orally.

63. The method according to claim 62, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg / day to 50 mg / day.

64. The method according to claim 63, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of 25 mg.

65. A compound of formula (I): (I) Or a pharmaceutically acceptable salt thereof, used in the treatment method according to any one of claims 1 to 64.

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