Treatment for autism spectrum disorder

Abstract

To provide a pharmaceutical composition and a kit for treating autism spectrum disorder (ASD) that exhibit measurable physiological effects in a patient.SOLUTION: A pharmaceutical composition comprising ibudilast and bumetanide as active ingredients for use in the treatment of autism spectrum disorder (ASD) is provided. The treatment induces favorable changes in the EEG of the patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions, kits and methods for treating autism spectrum disorders. [Background technology]

[0002] Autism spectrum disorders (ASDs) comprise a group of lifelong neurodevelopmental abnormalities that, according to recent estimates, adversely affect 1.5% of the population in developed countries. According to the current diagnostic criteria, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), individuals with ASD must exhibit deficits in social interaction and communication and at least two of four subdomains of restricted or repetitive behaviors. ASD symptoms must cause clinically significant impairment and adversely affect the patient's ability to interact with others, particularly with peers during adolescence.

[0003] Largely due to a lack of objective criteria for defining previous subtypes, including Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS), the current edition of DSM-5 has eliminated the classification of ASD subtypes and grouped them under a single umbrella. However, ASD remains characterized by high variability in behavioral symptoms and a highly complex genetic basis, which suggests the existence of ASD subtypes. Therefore, efforts to classify ASD remain critically important and must rely on defining the relationship between clinical symptoms and biological mechanisms to improve clinical trial outcomes.

[0004] To date, the first biologically defined subgroup of patients with ASD, ASD Phenotype 1 (ASD-Phen1), has been identified. These patients are characterized by the presence of specific non-behavioral clinical signs and symptoms (CSSs) that reflect the effects of hyperactivation of the NRF2 gene and its associated pathways (WO2019 / 086722A1). Subsequently, STP1, a combination of ibudilast and bumetanide, was identified as a potential tailored treatment for ASD-Phen1 (EP3785733B1).

[0005] Ibudilast is a brain-penetrant inhibitor of phosphodiesterases 3 (PDE3), 4 (PDE4), 10 (PDE10), and 11 (PDE11). Bumetanide is an inhibitor of NKCC1 / NKCC2. At the physiological level, increased expression and activation of NKCC1 may lead to intracellular chloride accumulation, antagonizing gamma-aminobutyric acid (GABA) currents in neurons, thereby reducing inhibition and increasing excitation. This increased neuronal excitation may then lead to abnormal activity in neuronal networks, adversely affecting patient behavior. To compensate for this indirect effect of ibudilast, we proposed combining ibudilast with the NKCC1 inhibitor bumetanide for the treatment of patients with ASD.

[0006] However, the actual impact of STP1 in ASD patients remains poorly explained. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, the desired technical problem is to provide a treatment for ASD that shows a measurable physiological effect in patients. [Means for solving the problem]

[0008] In one aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients ibudilast and bumetanide for use in the treatment of autism spectrum disorder (ASD), wherein said treatment induces favorable changes in the EEG of a patient.

[0009] In another aspect, the present invention relates to a kit comprising a dosage form comprising ibudilast and a dosage form comprising bumetanide for use in treating autism spectrum disorder (ASD), wherein the treatment induces at least one favorable change in the EEG of a patient.

[0010] In yet another aspect, the present invention relates to a method of treating an autism spectrum disorder (ASD), wherein said treatment induces favorable changes in the EEG of a patient. [Brief explanation of the drawings]

[0011] Figures 1a and 1b show the effect of STP1 on gamma waves. [Figure 1a] Absolute power of gamma waves 2 after administration of 5 / 1 mg STP1, after administration of 10 / 1 mg STP1, and after administration of placebo twice daily in ASD-Phen1 patients on day 14. [Figure 1b] Gamma wave power (dB) in the frontal and entorhinal regions of the brain on day 14 for placebo (N=3), 5 / 1 mg STP1 (N=6), and 10 / 1 mg STP1 (N=3). Each value is normalized to the baseline value before administration.

[0012] [Figure 2] Figure 2 shows that complex synchronization analysis showing increased ITC signals suggests increased neural synchronization activity to auditory chirp signals measured in placebo (N=2) and 10 / 1 mg STP1 (N=3) on days 1 and 14 post-dose.

[0013] Figures 3a and 3b show the effect of STP1 on alpha waves. [Figure 3a] Absolute alpha1 and alpha2 power after 5 / 1mg STP1, 10 / 1mg STP1, and twice-daily placebo in ASD-Phen1 on day 14. [Figure 3b] Alpha 2 (relative) in brain regions at day 14 for placebo (N=3), 5 / 1 mg STP1 (N=6), and 10 / 1 mg STP1 (N=3). DETAILED DESCRIPTION OF THE INVENTION

[0014] In one aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients ibudilast and bumetanide for use in the treatment of autism spectrum disorder (ASD), wherein said treatment induces favorable changes in the EEG of a patient.

[0015] In another aspect, the present invention relates to a kit comprising a dosage form comprising ibudilast and a dosage form comprising bumetanide for use in the treatment of autism spectrum disorder (ASD), wherein said treatment induces favorable changes in the EEG of a patient.

[0016] In yet another aspect, the present invention relates to a method for treating autism spectrum disorder (ASD), wherein the treatment induces favorable changes in a patient's EEG. In a preferred embodiment, the treatment comprises administering a pharmaceutical composition comprising ibudilast and bumetanide as active ingredients. In another preferred embodiment, the treatment comprises co-administration of a dosage form comprising ibudilast and a dosage form comprising bumetanide.

[0017] According to the present invention, the two active ingredients, ibudilast and bumetanide, can both be provided in a single pharmaceutical composition or can be provided as a kit containing separate dosage forms for each active ingredient.

[0018] A kit is defined herein as a combination product containing several individual dosage forms provided in a package that exhibit complementary effects when applied simultaneously, and in this respect the effects achieved by a kit are similar to those achieved by a pharmaceutical composition.

[0019] The pharmaceutical compositions of the present invention have the advantage of reducing the number of dosage forms that must be administered to a patient, thereby improving patient compliance. Furthermore, providing the active ingredients in defined dosage forms ensures that the correct dosage of each active ingredient is administered simultaneously.

[0020] In the kit of the present invention, the amount of each active ingredient can be individually adjusted according to the specific requirements of different age groups or in conjunction with a personalized treatment plan.

[0021] As used herein, the term autism spectrum disorder (ASD) is understood to encompass a family of neurodevelopmental disorders characterized by deficits in social communication and interaction, and restricted and repetitive patterns of behavior, interests, or activities. Hereinafter, the terms "autism spectrum disorder," "autism," and "ASD" are used interchangeably.

[0022] As used herein, the term "patient" refers to an "ASD patient" and is intended to include not only those diagnosed with ASD, but also those suspected of having ASD.

[0023] Those skilled in the art are well aware of how a patient can be diagnosed with ASD.

[0024] For example, a person skilled in the art may diagnose a subject with ASD according to the criteria set forth in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Fifth Edition. Similarly, an ASD patient may be diagnosed based on standardized assessment tools, including ADOS, ADI-R, CARS, DISCO, or M-CHAT.

[0025] In other cases, patients may have an established DSM-IV diagnosis of autism, Asperger's syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS).

[0026] Additionally, the present invention may be useful for patients who meet one or more of the following criteria: persistent deficits in social communication and social interaction across multiple settings, currently or previously manifested by: restricted and repetitive patterns of behavior, interests, or activities, currently or previously manifested by at least two of the following: symptoms present in early development (but may not fully manifest until social demands exceed limited capabilities or may be masked by learned strategies later in life); symptoms causing clinically significant impairment in social, occupational, or other important areas of current functioning; impairments not adequately explained by intellectual disability (intellectual developmental disorder) or global developmental delay.

[0027] ASD may occur with or without intellectual disability and / or language impairment, and may be associated with known medical or genetic conditions or environmental factors, or with other neurodevelopmental, psychiatric, or behavioral disorders.

[0028] ASD can occur at various levels of severity, which may be classified in terms of social-communicative dysfunction and restricted and repetitive behaviors. The present invention may be applied to patients suffering from ASD of any severity.

[0029] In one embodiment, the pharmaceutical composition or kit according to the invention is for use in the treatment of ASD in a subgroup of ASD patients referred to as ASD phenotype 1 patients.

[0030] As used herein, the terms "ASD phenotype 1" and "phenotype 1" are used interchangeably.

[0031] In one embodiment, a patient with ASD phenotype 1 is diagnosed as a phenotype 1 patient by a diagnosis of ASD and by the presence of the following clinical signs and symptoms: Enlarged head size, defined as a head circumference equal to or greater than the 75th percentile on the CDC growth chart at any time before age 24 months; Systematic aggravation of ASD behavioral symptoms during immune-induced episodes such as fever, infectious events, and acute inflammation; and / or Negative response to a challenge with an NRF2 activator such as sulforaphane.

[0032] The presence or absence of these clinical signs and symptoms may be determined with the aid of a standardized questionnaire answered by the patient or caregiver. In a preferred embodiment, patients with ASD phenotype 1 exhibit all clinical signs and symptoms.

[0033] Patients with ASD phenotype 1 may be identified with the aid of a challenge test, as described in WO2019 / 086722A1. Briefly, the concept of challenge testing is based on administering an Nrf2 activator to ASD patients. In patients with ASD phenotype 1 who already exhibit increased expression of each pathway, further activation of NRF2 leads to an exacerbation of core symptoms. Therefore, patients with ASD phenotype 1 may be identified by a negative behavioral response to challenge testing.

[0034] The pharmaceutical compositions and kits of the present invention comprise ibudilast, an oral anti-inflammatory and neuroprotective agent that is metabolized primarily by the liver and has the chemical structure of Formula I: [ka]

[0035] Ibudilast is a phosphodiesterase (PDE) inhibitor, primarily inhibiting PDE4. Its clinical efficacy has been demonstrated for bronchial asthma and cerebrovascular disease. Ibudilast is currently undergoing clinical trials in the United States for progressive multiple sclerosis, as well as other diseases such as amyotrophic lateral sclerosis and drug addiction (code: AV-411 or MN-166).

[0036] The dosage forms of the pharmaceutical compositions or kits of the present invention contain between 2.5 mg and 50 mg of ibudilast and are administered twice daily, so that the total daily dose of ibudilast in the treatment of the present invention is between 5 mg and 100 mg of ibudilast. In preferred embodiments, the dosage forms of the pharmaceutical compositions or kits contain 5 mg or 10 mg of ibudilast, so that ibudilast is preferably administered at a total daily dose of 10 mg or 20 mg.

[0037] The pharmaceutical compositions and kits of the present invention further comprise bumetanide, also known as 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. Bumetanide is an inhibitor of NKCC1 and acts as a loop diuretic. It is available under trade names such as bumex and burinex. Its chemical structure is represented by Formula II below. [ka]

[0038] The dosage forms of the pharmaceutical compositions or kits of the present invention contain between 0.25 mg and 5 mg of bumetanide and are administered twice daily, so that the total daily dose of bumetanide in the treatment of the present invention is between 0.5 mg and 10 mg of bumetanide. In a preferred embodiment, the dosage forms of the pharmaceutical compositions or kits of the present invention contain 1 mg of bumetanide, so that bumetanide is preferably administered at a total daily dose of 2 mg.

[0039] In some embodiments, instead of bumetanide itself, the pharmaceutical composition or kit dosage form of the present invention includes a bumetanide derivative, such as AqB007, AqB011, PF-2178, BUM13, BUM5, or bumepamine.

[0040] The pharmaceutical compositions and kits of the present invention induce favorable changes in the electroencephalogram (EEG) of a patient.

[0041] An EEG is a recording of electrical activity in a subject's brain, recorded at rest or after stimulation. The observed signals are classified by frequency: alpha (8-13 Hz), beta (13-30 Hz), gamma (25-140 Hz), delta (0.5-4 Hz), and theta (4-7 Hz). Healthy human brains exhibit specific activity patterns on the EEG, which correlate with the individual's state of wakefulness and the activities they are engaged in. Comparing the intensity and type of activity in specific brain regions allows for the identification of normal versus abnormal brain function in patients. Although abnormal patterns do not necessarily lead to symptoms, subclinical electroencephalographic abnormalities (SEA) in ASD may be associated with changes in intellectual function, dysfunctional behavior, and disease severity.

[0042] A favorable change in EEG is therefore defined as any change in EEG that causes the EEG pattern in a particular brain region or during a particular activity to more closely resemble the pattern observed in age- and sex-matched typically developing controls.

[0043] Different parts of the brain are associated with different functions. For example, one or more brain regions are associated with cognition, including thinking, reasoning, problem-solving, memory, and language; sensory processing, such as hearing, vision, taste, smell, or touch; motor control; memory, including short-term (working) and long-term (procedural) memory; sleep and wakefulness; language processing, including comprehension and communication; learning and adaptability; emotion; and social and behavioral functions.

[0044] Executive functions are higher-level cognitive processes that enable individuals to plan, organize, set goals, switch tasks, and monitor their behavior. Executive functions are primarily controlled by the prefrontal and frontal cortices, but also by additional cortical regions, including the anterior anterior cingulate cortex, lateral parietal cortex, as well as the basal ganglia and hippocampus.

[0045] Language comprehension is controlled by various brain regions, including Wernicke's area in the left superior temporal region and the angular gyrus in the parietal lobe. Language comprehension is also part of a broader network of language processing that involves the temporal, frontal, and parietal lobes.

[0046] Memory acquisition and processing involves multiple brain regions working together to encode, consolidate, store, and retrieve memories, including the hippocampus, cerebellum, temporal and superior temporal cortex, and parietal cortex.

[0047] In one embodiment, the brain region associated with executive function is the left frontal pole and / or the right frontal pole. In one embodiment, the brain region associated with language comprehension and / or memory processing is the superior temporal region. In one embodiment, the brain region associated with memory processing is the entorhinal cortex. In one embodiment, the brain region associated with working memory function is the left superior area and / or the isthmus cingulate. In one embodiment, the brain region associated with sensory function is the paracentral region.

[0048] In a preferred embodiment, the favorable change in the EEG comprises a decrease in gamma waves in brain regions associated with executive function, language comprehension, and memory processing, i.e., the left and / or right frontal pole, the superior temporal region, and / or the entorhinal cortex. In a particularly preferred embodiment, gamma waves in each brain region are reduced by 30% to 50% in terms of relative power. Thus, in one embodiment, the favorable change in the EEG comprises a 30% to 50% decrease in gamma waves, expressed as relative power, in the left and / or right frontal pole. In one embodiment, the favorable change in the EEG comprises a 30% to 50% decrease in gamma waves, expressed as relative power, in the superior temporal region. In one embodiment, the favorable change in the EEG comprises a 30% to 50% decrease in gamma waves, expressed as relative power, in the entorhinal cortex. In particularly preferred embodiments, favorable changes in the EEG include a 30% to 50% reduction in gamma waves in the left and right frontal poles, superior temporal region, and entorhinal cortex.

[0049] Elevated gamma oscillations are associated with altered sensory processing of stimulus characteristics and are thought to primarily reflect localized abnormal neural interactions caused by an imbalance between excitatory interactions on parvalbumin-positive (inhibitory) interneurons and inhibition arising from parvalbumin-positive interneurons. Persistent excitatory GABA activity suggests that the ability to synchronize gamma power may be specifically impaired in individuals with ASD, as previously suggested for individuals with Fragile X syndrome. This pattern of increased high-total frequency (gamma) neural activity and decreased temporally synchronized, spatially focused neural activity may have broad neurobehavioral implications in addition to its impact on sensory processing. Because gamma frequencies are in the primary working frequency range of the human auditory system, they can be used to assess the synchronization or desynchronization of neural responses to the oscillatory frequency of sensory stimuli. Neural activity at gamma frequencies has been successfully investigated using chirp stimuli with linearly increasing frequencies from 1 Hz to 100 Hz.

[0050] In another embodiment, the favorable change in EEG comprises an increase in alpha waves in brain regions associated with working memory and sensory function, i.e., the left parietal region, the cingulate isthmus, and / or the paracentral region. In a particularly preferred embodiment, the increase in alpha waves in each brain region, expressed in relative power, is between 20% and 40%. Thus, in one embodiment, the favorable change in EEG comprises a 20% to 40% increase in alpha waves, expressed in relative power, in the left parietal region. In one embodiment, the favorable change in EEG comprises a 20% to 40% increase in alpha waves, expressed in relative power, in the cingulate isthmus. In one embodiment, the favorable change in EEG comprises a 20% to 40% increase in alpha waves, expressed in relative power, in the paracentral region. In a particularly preferred embodiment, the favorable change in EEG comprises a 20% to 40% increase in alpha waves, expressed in relative power, in the left parietal region, the cingulate isthmus, and the paracentral region.

[0051] In another preferred embodiment, the favorable changes in the EEG include both a 30% to 50% decrease in gamma oscillations, as expressed by relative power, in the left and right frontal poles, superior temporal region, and entorhinal cortex, and a 20% to 40% increase in alpha oscillations, as expressed by relative power, in the left parietal region, cingulate isthmus, and paracentral region.

[0052] In one embodiment, treatment with a composition or kit of the present invention results in increased auditory sensory processing via increased neural acoustic synchronization (or phase-locking) to external auditory or chirp stimuli, compared to gamma-band phase-locking prior to treatment. One method for measuring increased auditory sensory processing is as follows: The patient listens to an auditory chirp stimulus generated using a 1000 Hz tone whose amplitude is modulated by a sine wave whose frequency increases linearly from 1 Hz to 100 Hz over a 2-second period. Auditory cortical signals are detected using sensors distributed across the fronto-central scalp. Morlet wavelets are then applied to analyze time-frequency, single trial power (STP), and inter-trial coherence (ITC). An increase in ITC indicates increased neural synchronization to the auditory chirp.

[0053] While not intending to be bound by a particular mechanism, the inventors believe that a reduction in gamma waves in fronto-central regions leads to an increase in auditory sensory processing. Accordingly, in one embodiment, the present invention relates to a pharmaceutical composition comprising ibudilast and bumetanide as active ingredients, or a kit comprising a dosage form comprising ibudilast and a dosage form comprising bumetanide, for use in the treatment of autism spectrum disorder (ASD), wherein the treatment induces favorable changes in EEG, including a 30% to 50% decrease in gamma waves, as expressed by relative power, in brain regions associated with executive function, language comprehension, and memory processing, and the treatment results in an increase in auditory sensory processing via neural auditory synchronization to external auditory stimuli.

[0054] The pharmaceutical compositions and kits of the present invention are the first pharmacological treatments available for the treatment of ASD that not only improve symptoms but also induce quantifiable changes in the EEG.

[0055] The kit of the present invention is for use in treating ASD, wherein the two dosage forms are administered simultaneously. The pharmaceutical composition and dosage forms are administered twice daily (bid).

[0056] The dosage form of the pharmaceutical compositions and kits of the present invention is preferably an oral dosage form (e.g., tablet, capsule, pill, sachet, powder, drop, emulsion, gel, gum, liquid, lyophilized product, paste, solution or suspension), most preferably a tablet, capsule or pill.

[0057] It is also contemplated by the present invention that the dosage form of the pharmaceutical composition or kit of the present invention may further comprise a pharmaceutically acceptable carrier or excipient, such as a lubricant, disintegrant, adhesive, anti-adherent, binder, preservative, filler, adsorbent, or solvent.

[0058] The pharmaceutical compositions and dosage forms of the present invention may be formulated as immediate release or sustained-release / modified-release formulations. In a preferred embodiment, the dosage form containing ibudilast is a modified-release formulation, and the dosage form containing bumetanide is an immediate-release formulation. In one embodiment, the active ingredients in the pharmaceutical compositions of the present invention are formulated differently, i.e., ibudilast is formulated in a modified-release formulation, and bumetanide is formulated in an immediate-release formulation. [Example]

[0059] Effect of 2 weeks of treatment with STP1 in patients with ASD-Phen1

[0060] Patients were eligible to participate in the study if they met all of the following inclusion criteria: 1) Male or female individuals between the ages of 18 and 40 years, including those with a previous diagnosis of ASD (based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, confirmed by medical history and interview with an autism diagnostic specialist (CE)). 2) Well-documented enlargement of head size, defined as head circumference equal to or greater than the 75th percentile on the CDC growth chart, at any time before age 24 months, or a diagnosis of macrocephaly. 3) Systematic worsening of ASD behavioral symptoms, so-called flares, occurred during episodes of immune provocation (e.g., acute inflammation, such as fever and infectious events), as assessed by the ASD-Phen1 semi-structured interview form.

[0061] A total of 12 patients (median age: 19.2 years) were screened for study eligibility, of whom 12 (100.0%) were randomly assigned to receive treatment with 5 / 1 mg STP1 (i.e., 5 mg ibudilast-1 mg bumetanide; n=6) or placebo (n=2) in cohort 1 and 10 / 1 mg STP1 (i.e., 10 mg ibudilast-1 mg bumetanide; n=3) or placebo (n=1) in cohort 2.

[0062] Cohort 1 received 5 / 1 mg STP1 orally twice daily (5 mg ibudilast and 1 mg bumetanide, n=6) or placebo (n=2). Cohort 2 received 10 / 1 mg STP1 orally twice daily (10 mg ibudilast and 1 mg bumetanide, n=3) or matching oral placebo twice daily (n=1).

[0063] The two drugs (ibudilast and bumetanide) were taken simultaneously with food and water, with two daily doses spaced approximately 6 hours apart.

[0064] STP1 induced statistically significant dose-dependent reductions in gamma oscillations compared to placebo in target brain regions related to executive function (left and right frontal poles) and memory (left and right entorhinal cortex) (Figures 1a and 1b). In particular, significant effects were observed in target brain regions related to social cognition and emotional processing: the left and right frontal poles (executive function), the left and right entorhinal regions (memory-related processing), and the left and right superior temporal regions.

[0065] For chirp signal analysis, 10 of the 12 patients with complete data sets were evaluated. Two patients did not complete the baseline chirp EEG. Responses included intertrial phase coherence (ITC; 40 Hz, 80 Hz, onset, and end) and single trial power (STP; alpha, gamma 1, and gamma 2). Elevated ITC suggests increased neural synchronization to the auditory chirp signal. STP refers to the background spectral power in the auditory chirp signal. ITC values ​​were estimated from the time-frequency analysis of the chirp signal response shown in Figure 2.

[0066] Mean scores provided in the 10 / 1 mg STP1 group (N=3) relate to changes from baseline to either Day 1 (acute phase after administration), Day 14, or Day 28. Mean scores for the Day 14 follow-up included 40 Hz ITC (0.008, SD=0.086), 80 Hz ITC (0.030, SD=0.053), and mean STP scores for the Day 14 follow-up included Alpha (-1.3, SD=6.8), Gamma 1 (-2.1, SD=2.7), and Gamma 2 (-2.6, SD=1.7). Overall, as seen in Figure 2, there was a clear numerical increase in neural synchronization for 80 Hz ITC.

[0067] Treatment with STP1 showed a significant increase in alpha2 power in frontal and occipital regions, as well as in brain regions associated with memory function (right frontal pole, right cingulate isthmus) and sensation (right paracentral region) (Figures 3a and 3b).

Claims

1. 1. A pharmaceutical composition comprising ibudilast and bumetanide as active ingredients for use in the treatment of autism spectrum disorder (ASD), wherein said treatment induces favorable changes in the EEG of a patient.

2. 1. A kit comprising a dosage form comprising ibudilast and a dosage form comprising bumetanide for use in the treatment of autism spectrum disorder (ASD), wherein the treatment induces at least one favorable change in the EEG of a patient.

3. 3. The composition for use of claim 1 or the kit for use of claim 2, wherein the favorable changes in the EEG include a decrease in gamma waves in brain regions associated with executive function, language comprehension and memory processing.

4. 4. The composition or kit for use according to claim 3, wherein the brain region associated with executive function is the left frontal pole and / or the right frontal pole.

5. 5. A composition or kit for use according to claim 3 or claim 4, wherein the brain region associated with language comprehension and memory processing is the superior temporal region.

6. 6. A composition or kit for use according to any one of claims 3 to 5, wherein the brain region associated with memory processing is the entorhinal cortex.

7. 7. A composition or kit for use according to any one of claims 3 to 6, wherein the gamma waves, expressed as relative power in each brain region, are reduced by 30% to 50%.

8. 8. A composition or kit for use according to any one of claims 1 to 7, wherein the favourable changes in the EEG include an increase in alpha 2 power in brain regions associated with working memory and sensory function.

9. 9. The composition or kit for use according to claim 8, wherein the brain region associated with working memory function is the left parietal region and / or the cingulate isthmus.

10. 10. A composition or kit for use according to claim 8 or claim 9, wherein the brain region associated with sensory function is the paracentral region.

11. 11. A composition or kit for use according to any one of claims 8 to 10, wherein alpha2, expressed as relative power, is increased by 20% to 40% in each of said brain regions.

12. 12. A composition or kit for use according to any one of claims 1 to 11, wherein the treatment results in enhanced auditory sensory processing via neural auditory synchronization to external auditory stimuli.

13. 13. A composition or kit for use according to any one of claims 1 to 12, wherein the composition or dosage form is to be administered twice daily.

14. 14. A composition or kit for use according to any one of claims 1 to 13, wherein the composition or the dosage form is an oral dosage form.

15. 15. A composition or kit for use according to any one of claims 1 to 14, wherein the treatment comprises a total daily dose of ibudilast between 5 mg and 30 mg and / or a total daily dose of bumetanide between 0.5 mg and 10 mg.

16. 16. A composition or kit for use according to any one of claims 1 to 15, wherein the treatment comprises a total daily dose of ibudilast between 10 mg and 20 mg and / or a total daily dose of bumetanide of 2 mg.

17. 17. A composition or kit for use according to any one of claims 1 to 16, wherein the patient is a patient with ASD phenotype 1.

18. The patient is diagnosed with ASD and - diagnosed with enlarged head size, defined as a head circumference equal to or greater than the 75th percentile on the CDC growth chart, at any time before age 24 months; - diagnosed with systematic worsening of ASD behavioral symptoms during immune-induced episodes such as fever, infectious events, and acute inflammation; and / or - A negative reaction was diagnosed to a stress test using an Nrf2 activator such as sulforaphane, The composition or kit for use according to claim 17, wherein the patient has been diagnosed as having ASD phenotype 1 by

Images