Treatment of autism spectrum disorders

Abstract

The invention relates to a pharmaceutical composition comprising ibudilast and bumetanide as active ingredients for use in the treatment of autism spectrum disorders (ASD), wherein the treatment induces favorable changes in the patient's EEG. Figure for abstract: Fig. 1a

Description

Title of the invention: Treatment of autism spectrum disorders Field of invention

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

[0002] Context

[0003] Autism spectrum disorders (ASD) comprise a group of lifelong neurodevelopmental disorders that, according to recent estimates, affect 1.5% of the population in developed countries. According to the current diagnostic criteria of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition), an individual with ASD must have deficits in social interaction and communication, associated with at least two of the four subdomains of restricted or repetitive behaviors. The manifestations of ASD must cause clinically significant impairment, affecting the patients' ability to interact with others, particularly with their same-aged peers in their youth.

[0004] The current version of DSM-5 has abandoned the classifications of ASD subtypes to group them under a single umbrella, mainly due to the lack of objective criteria to define previous subtypes, including Asperger's Disorder and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). However, ASD remains characterized by great heterogeneity in its behavioral manifestations with very complex genetic underpinnings, suggesting the existence of ASD subtypes. Therefore, efforts to categorize ASD are still of crucial importance and must rely on defining a relationship between clinical symptoms and biological mechanisms to improve clinical trial outcomes.

[0005] Previously, a first biologically defined subgroup of ASD patients, ASD phenotype 1 (ASD-Phenl), was identified, with patients characterized by the presence of specific, non-behavioral clinical signs and symptoms (CSS) reflecting the effects of overactivation of the NRF2 gene and its associated pathways (WO 2019 / 086722 A1). STP1, a combination of ibudilast and bumetanide, was subsequently identified as a potential tailor-made treatment for the ASD-Phenl group (EP 3785733 B1).

[0006] 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 can lead to the accumulation of chlorine in cells and antagonize gamma-aminobutyric acid (GABA) current in neurons, thus decreasing inhibition and promoting excitation. This increased neuronal excitation can then lead to aberrant activity of the neuronal network and affect the patient's behavior. To compensate for this indirect effect of ibudilast, we proposed combining ibudilast with bumetanide, an NKCC1 inhibitor, for the treatment of patients with ASD.

[0007] However, the actual effects of STP1 on patients with ASD have not yet been well described.

[0008] Objective technical problem

[0009] The objective technical problem is therefore to propose a treatment for ASD which presents measurable physiological effects in patients. Summary of the invention

[0010] In one aspect, the invention relates to a pharmaceutical composition comprising ibudilast and bumetanide as active ingredients for use in the treatment of autism spectrum disorders (ASD), wherein the treatment induces favorable changes in the patient's EEG.

[0011] In another aspect, the 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 disorders (ASD), the treatment inducing at least one favorable change in the patient's EEG.

[0012] In yet another aspect, the invention relates to a method of treating autism spectrum disorders (ASD), the treatment inducing favorable changes in the patient's EEG. Brief description of the figures

[0013] Figure 1 shows the effect of STP1 on gamma waves, a) Absolute Gamma 2 power after administration of STP1 5 / 1 mg, STP1 10 / 1 mg and placebo BID in the ASD-Phenl group on day 14; b) Gamma 1 power (dB) in frontal and entorhinal brain regions on day 14 in placebo (N = 3), STP1 5 / 1 mg (N = 6) and STP1 10 / 1 mg (N = 3). Each value is normalized to pre-dose.

[0014] [Fig.2] shows that the complex synchronization analysis showing an increased ITC signal indicates increased neuronal synchronization with the auditory chirp measured in placebo N = 2 and STP1 10 / 1 mg N = 3 at day 1 post-dose and day 14.

[0015] Figure 3 shows the effect of STP1 on alpha waves, a) Absolute power of Alpha 1 and Alpha 2 after administration of STP1 5 / 1 mg, STP1 10 / 1 mg and placebo BID in the ASD-Phenl group on day 14; b) Alpha 2 (relative) in brain regions on day 14 in placebo (N=3), STP1 5 / 1 mg (N=6) and STP1 10 / 1 mg (N=3). Detailed description

[0016] In one aspect, the invention relates to a pharmaceutical composition comprising ibudilast and bumetanide as active ingredients for use in the treatment of autism spectrum disorders (ASD), the treatment inducing favorable changes in the patient's EEG.

[0017] In another aspect, the 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 disorders (ASD), wherein the treatment induces favorable changes in the patient's EEG.

[0018] In yet another aspect, the invention relates to a method of treating autism spectrum disorders (ASD), the treatment inducing favorable changes in the 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 concomitantly administering a dosage form comprising ibudilast and a dosage form comprising bumetanide.

[0019] According to the invention, the two active ingredients, ibudilast and bumetanide, can be provided either in a single pharmaceutical composition or in the form of a kit comprising a separate dosage form for each active ingredient.

[0020] A kit is defined herein as a combination product provided in package form and containing several individual dosage forms which exhibit a complementary effect when applied together. In this respect, the effect achieved by a kit and a pharmaceutical composition are similar.

[0021] The pharmaceutical composition according to the invention has the advantage of reducing the number of dosage forms that need to be administered to a patient, thereby increasing patient compliance. In addition, providing the active ingredients in a fixed dosage form ensures that the correct dosages of each active ingredient are administered together.

[0022] In the kit according to the invention, the quantity of each active ingredient can be adjusted individually, according to the specific needs of different age groups or in line with personalized treatment plans.

[0023] As used herein, the term autism spectrum disorder (ASD) is understood to cover a family of neurodevelopmental disorders characterized by deficits in social communication and interaction and restricted and repetitive patterns of behavior, interests, or activities. In the following, the terms "autism spectrum disorder," "autism," and "ASD" are used interchangeably.

[0024] As used herein, the term "patient" refers to a "patient with ASD" and is intended to cover not only individuals diagnosed with ASD, but also individuals suspected of having ASD.

[0025] The person skilled in the art knows perfectly well how a patient can be diagnosed with an ASD.

[0026] For example, one skilled in the art may follow the criteria established in the "American Psychiatric Association; Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Fifth Edition" to give a subject a diagnosis of ASD. Similarly, patients with ASD may have been diagnosed according to standardized assessment tools, including ADOS, ADLR, CARS, DISCO, or M-CHAT.

[0027] In other cases, patients may have a well-established DSM-IV diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified (PDD-NOS).

[0028] In addition, the present invention may be useful for subjects meeting one or more of the following criteria: persistent deficits in social communication and social interaction in multiple contexts as manifested by the following, currently or in the past; restricted and repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or in the past; symptoms present in the early developmental period (but which may not become fully manifest until social demands exceed limited abilities, or may be masked by strategies learned later in life); the symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning;these disorders are not better explained by an intellectual deficiency (intellectual developmental disorder) or a global developmental delay.

[0029] ASD can occur with or without intellectual and / or language impairment. It may be associated with a known medical or genetic condition, an environmental factor, or other neurodevelopmental, mental, or behavioral disorders.

[0030] ASD can occur at different levels of severity which can be classified according to the impairment of social communication and in terms of restricted and repetitive behavior. The present invention can be applied to patients suffering from any level of severity of ASD.

[0031] In one embodiment, the pharmaceutical composition or kit according to the present invention is for use in the treatment of ASD in a subgroup of ASD patients referred to as phenotype 1 ASD patients.

[0032] As used herein, the terms "phenotype 1 ASD" and "phenotype 1" are used interchangeably.

[0033] In one embodiment, patients with phenotype 1 ASD are diagnosed as phenotype 1 patients by a diagnosis of ASD and the presence of the following clinical signs and symptoms: - an enlarged head size at any time after birth and before 24 months of age, defined as a head circumference > 75th percentile in the CDC growth chart, - a consistent worsening of ASD behavioral symptoms during episodes of immune challenges, e.g., fever, infectious events, and acute inflammation, and / or - a negative reaction to a challenge test with an Nrf2 activator such as sulforaphane.

[0034] The presence or absence of these clinical signs and symptoms can be determined using standardized questionnaires to be completed by the patient or a caregiver. In a preferred embodiment, the patient with phenotype 1 ASD exhibits all clinical signs and symptoms.

[0035] Patients with ASD phenotype 1 can be identified using a challenge test as described in WO 2019086722 AL In a nutshell, the concept of a challenge test is based on administering an Nrf2 activator to a patient with ASD. In patients with ASD phenotype 1, who already show upregulation of the respective pathways, further activation of Nrf2 will lead to worsening of the core symptoms. Therefore, patients with ASD phenotype 1 can be identified by a negative behavioral response to a challenge test.

[0036] The pharmaceutical composition and kit according to the invention comprise ibudilast. Ibudilast is an oral anti-inflammatory and neuroprotective agent, metabolized mainly by the liver, having the following chemical structure of formula I

[0037] Ibudilast is a phosphodiesterase (PDE) inhibitor, primarily inhibiting PDE4. The clinical efficacy of ibudilast has been proven in bronchial asthma and cerebrovascular disorders. Ibudilast is currently undergoing clinical trials clinics in the United States for the treatment of progressive multiple sclerosis and other conditions such as amyotrophic lateral sclerosis and substance dependence (codes: AV-411 or MN-166).

[0038] The pharmaceutical composition or dosage form of the kit according to the invention comprises between 2.5 mg and 50 mg of ibudilast and is administered twice daily, such that the total daily dose of ibudilast in the treatment according to the invention is between 5 and 100 mg of ibudilast. In preferred embodiments, the pharmaceutical composition or dosage form of the kit comprises 5 or 10 mg of ibudilast, such that ibudilast is preferably administered at a total daily dose of 10 or 20 mg.

[0039] The pharmaceutical composition and kit according to the invention also comprise bumetanide, also known as 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. Bumetanide is an NKCC1 inhibitor and acts as a loop diuretic. It is available under the trade names bumex and burinex, among others. Its chemical structure is represented below by formula II

[0040] The pharmaceutical composition or dosage form of the kit according to the invention comprises between 0.25 mg and 5 mg of bumetanide and is administered twice daily, such that the total daily dose of bumetanide in the treatment according to the invention is between 0.5 and 10 mg of bumetanide. In a preferred embodiment, the pharmaceutical composition or dosage form of the kit comprises 1 mg of bumetanide, such that bumetanide is preferably administered at a total daily dose of 2 mg.

[0041] In some embodiments, instead of bumetanide itself, the pharmaceutical composition or dosage form of the kit according to the invention comprises bumetanide derivatives, such as AqB007, AqBOll, PF-2178, BUM13, BUM5 or bumepamine.

[0042] The pharmaceutical composition and the kits according to the invention induce a favorable evolution of the patient's electroencephalogram (EEG).

[0043] An EEG is a recording of electrical activity in a subject's brain, recorded, for example, at rest or after stimulation. The signals observed can be grouped according to frequency and divided into alpha (8-13 Hz), beta (13-30 Hz), gamma (25-140 Hz), delta (0.5-4 Hz), and theta (4-7 Hz) waves. A healthy human brain exhibits certain patterns of activity in the EEG that correlate with the person's wakefulness as well as the activities they are engaged in. Comparing the intensity and type of activity in certain areas of the brain helps determine a patient's normal and abnormal brain function. While an abnormal pattern may not necessarily translate into symptoms, in the case of ASD, subclinical electroencephalographic (EEG) abnormalities may nevertheless be associated with changes in intellectual functioning, dysfunctional behavior, and severity of the condition.

[0044] Favorable changes in the EEG are therefore defined as any change in the EEG that makes the EEG pattern in a certain area of ​​the brain or during a certain activity more similar to that observed in a normally developing control of the same age and sex.

[0045] Different parts of the brain are associated with different functionalities. For example, one or more areas of the brain are associated with cognition, including thinking, reasoning, problem solving, memory, language; sensory processing such as hearing, sight, taste, smell, or touch; motor control; memory, including short-term (working memory) and long-term (procedural memory); sleep and wakefulness; language processing, including comprehension and communication; learning and plasticity; emotions; social and behavioral functions.

[0046] Executive functions are higher-order cognitive processes that allow individuals to plan, organize, set goals, switch between tasks, and monitor their own behavior. Executive functions are primarily controlled by the prefrontal and frontal cortex, but also by the supplementary cortex comprising the frontal anterior cingulate cortex, the lateral parietal cortex, as well as the basal ganglia and the hippocampus.

[0047] Language comprehension is controlled by various areas of the brain, including Wernicke's gyrus, located in the left superior temporal region, and the angular gyrus located in the parietal lobe. Language comprehension is also part of language processing, which involves a larger network including the temporal, frontal, and parietal lobes.

[0048] Memory acquisition and processing involves multiple brain areas working together to encode, consolidate, store, and retrieve memories. These brain areas include the hippocampus, cerebellum, temporal and superior temporal cortex, and parietal cortex.

[0049] In one embodiment, the brain area associated with executive function is the left and / or right frontal pole. In one embodiment, the brain area associated with language comprehension and / or memory processing is the superior temporal region. In one embodiment, the brain area associated with memory processing is the entorhinal cortex. In one embodiment, the brain area associated with working memory function is the left superior zone and / or the cingulate isthmus. In one embodiment, the brain area associated with sensory function is the paracentral region.

[0050] In a preferred embodiment, the favorable change in the EEG comprises a reduction in gamma waves in brain areas 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, the gamma waves in the respective brain areas are reduced by 30 to 50% expressed as relative power. Thus, in one embodiment, the favorable change in the EEG comprises a reduction in gamma waves by 30 to 50% expressed as relative power in the left and / or right frontal pole. In one embodiment, the favorable change in the EEG comprises a reduction in gamma waves by 30 to 50% expressed as relative power in the superior temporal region.In one embodiment, the favorable change in the EEG comprises a reduction in gamma waves of 30-50% expressed as relative power in the left and / or right frontal pole. In a particularly preferred embodiment, the favorable change in the EEG comprises a reduction in gamma waves of 30-50% expressed in the left and right frontal pole, the superior temporal region and the entorhinal cortex.

[0051] High gamma waves have been associated with impaired sensory processing of stimulus features and are suspected to primarily reflect local abnormal neuronal interaction caused by the imbalance of excitatory interaction and inhibition originating from parvalbumin-positive interneurons (inhibitory neurons). The persistent excitatory GABA activity suggests that the ability to synchronize gamma power may be specifically reduced in patients with ASD, as previously suggested for patients with fragile X syndrome. Such a pattern of increased total high-frequency neuronal activity (gamma waves) but reduced temporally synchronous and spatially focused neuronal activity may have broad neurobehavioral implications in addition to its impact on sensory processing.Since gamma frequency is the main working frequency range of the human auditory system, it is possible to assess the desynchronization or synchronization of the response. neuronal activity at the oscillating frequency of the sensory stimulus. The use of a chirp stimulus whose frequency increases linearly from 1 to 100 Hz has been successfully used to examine neuronal activity in the gamma frequency.

[0052] In another embodiment, the favorable change in the EEG comprises an increase in alpha waves in brain areas associated with working memory function and sensory functions, i.e., in the left upper zone, the cingulate isthmus and / or the paracentral region. In a particularly preferred embodiment, gamma waves in the respective brain areas are reduced by 20 to 40% expressed as relative power. Thus, in one embodiment, the favorable change in the EEG comprises an increase in alpha waves by 20 to 40% expressed as relative power in the left upper zone. In one embodiment, the favorable change in the EEG comprises an increase in alpha waves by 20 to 40% expressed as relative power in the cingulate isthmus.In one embodiment, the favorable change in the EEG comprises an increase in gamma waves of 20 to 40% expressed as relative power in the paracentral region. In a particularly preferred embodiment, the favorable change in the EEG comprises an increase in alpha waves of 20 to 40% expressed as relative power in the left upper zone, the cingulate isthmus and the paracentral region.

[0053] In another preferred embodiment, the favorable change in the EEG includes both a reduction in gamma waves of 30 to 50% expressed as relative power in the left and right frontal pole, superior temporal region and entorhinal cortex and an increase in alpha waves of 20 to 40% expressed as relative power in the left superior zone, cingulate isthmus and paracentral region.

[0054] In one embodiment, treatment with the composition or kit of the invention results in increased auditory sensory processing by auditory neural synchronization (or increased phase locking) to an external auditory stimulus or chirp, the increase being compared to the gamma band phase locking before treatment. One way to measure the increase in auditory sensory processing is as follows: patients hear an auditory chirp stimulus generated using a 1000 Hz tone whose amplitude is modulated by a sinusoid whose frequency increases linearly from 1 to 100 Hz over 2 s. Signals from the auditory cortex are detected using sensors distributed over the frontocentral scalp. Analysis of time-frequency, single trial power (STP), and inter-trial coherence (ITC) is then performed by applying Morlet wavelets. The increase in ITC indicates increased neural synchronization with the auditory chirp..

[0055] Without wishing to be bound by a mechanism, the inventors believe that it is the reduction of gamma waves in the fronto-central area which leads to an increase in auditory sensory processing.Therefore, in one embodiment, the 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 disorders (ASD) for use in the treatment of ASD, wherein the treatment induces a favorable change in the EEG, wherein the favorable change comprises a reduction of gamma waves in brain areas associated with executive function, language comprehension and memory processing by 30-50% expressed as relative power and wherein the treatment results in increased auditory sensory processing by neuronal auditory synchronization to an external auditory stimulus.

[0056] The pharmaceutical compositions and kits according to the invention are the first drug interventions available for the treatment of ASD that not only lead to improvement in symptoms, but also induce quantifiable changes in the EEG.

[0057] The kits according to the invention are intended for use in the treatment of ASD, in which the two dosage forms are administered concomitantly. The pharmaceutical composition and the dosage forms are administered twice a day (bid).

[0058] The pharmaceutical compositions and dosage forms of the kit of the invention are preferably oral dosage forms, for example tablets, capsules, pills, sachets, powders, drops, emulsions, gels, gums, liquids, lyophilisates, pastes, solutions or suspensions, preferably tablets, capsules or pills.

[0059] It is also contemplated by the present invention that the pharmaceutical composition or dosage forms of the kit according to the present invention further comprise pharmaceutically acceptable carriers or excipients such as lubricants, disintegrants, adhesives, anti-adhesives, binders, preservatives, fillers, sorbents or vehicles.

[0060] The pharmaceutical composition and dosage forms of the invention may be formulated as immediate release formulations or extended / modified release formulations. In preferred embodiments, the dosage form comprising ibudilast is a modified release formulation and the dosage form comprising bumetanide is an immediate release formulation. In one embodiment, the active ingredients are formulated differently in the pharmaceutical composition according to the invention, i.e. Ibudilast is formulated for modified release and bumetanide is formulated for immediate release. Examples

[0061] Effect of 2-week treatment with STP1 in patients with ASD-Phenl

[0062] Patients were eligible to participate in the study if they met all of the following inclusion criteria: 1) Male or female, aged 18 to 40 years inclusive, with a previous diagnosis of ASD (according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-5] criteria confirmed by history and interview with an expert in autism diagnosis (EC); 2) well-documented enlarged head size at any time after birth and before 24 months of age, defined as a head circumference > 75th percentile of the CDC growth charts (12) or diagnosed with macrocephaly; 3) a systematic worsening of ASD behavioral symptoms, called flare-ups occurring during episodes of immune challenges (such as fever and infectious events, e.g., acute inflammation) as assessed by the ASD-Phenl semi-structured interview form.

[0063] A total of 12 patients (median age 19.2 years) were screened for study eligibility, of whom 12 (100.0%) were randomized to STP1 5 / 1 mg (i.e., ibudilast 5 mg - bumetanide 1 mg; n = 6) or placebo (n = 2) in cohort 1 and STP1 10 / 1 mg (i.e., ibudilast 10 mg - bumetanide 1 mg; n = 3) or placebo (n = 1) in cohort 2.

[0064] Cohort 1 received SPT1-5 / 1 mg orally bid (5 mg ibudilast and 1 mg bumetanide, n = 6) or placebo (n = 2). Cohort 2 received STP1-10 / 1 mg orally bid (10 mg ibudilast and 1 mg bumetanide, n = 3), or matching oral placebo twice daily (n = 1).

[0065] Both drugs (ibudilast and bumetanide) were taken at the same time with food and water, and the two daily doses were separated by approximately six hours.

[0066] In brain regions of interest associated with executive function (left and right frontal poles) and memory (left and right entorhinal regions), STP1 induced a statistically significant dose-dependent effect in reducing gamma power compared to placebo ([Fig. la] and [Fig. lb]). In particular, a significant effect was observed in brain regions of interest associated with social cognition and emotional processing for the left and right frontal poles (executive function), the left and right entorhinal regions (memory-related processes), and the left and right superior temporal region.

[0067] For Chirp analysis, 10 of the 12 subjects with complete datasets were considered. Two subjects did not perform a baseline chirp EEG. Responses include inter-trial phase coherence (ITC; 40 Hz, 80 Hz, onset and end) and single trial power (STP; alpha, gammal and gamma2). Increased ITC indicates increased neural synchronization with the auditory chirp. STP refers to the background spectral power during the auditory chirp. ITC values ​​are approximated from the time-frequency analysis of the chirp response shown in [Fig. 2].

[0068] In the STP1 10 / 1 mg group (N = 3), the mean score provided refers to the change from baseline to Day 1 (post acute dose), Day 14, and Day 28. The mean score for Day 14 follow-up includes ITC 40 Hz (0.008, SD = 0.086), ITC 80 Hz (0.030, SD = 0.053), STP mean scores for Day 14 follow-up include alpha (-1.3, SD = 6.8), gammal (-2.1, SD = 2.7), gamma2 (-2.6, SD = 1.7). Overall, there was a clear numerical increase in ITC 80 Hz neuronal synchronization as seen in [Fig.2].

[0069] Treatment with STP1 showed a significant increase in alpha 2 power in frontal and occipital regions and in brain areas associated with memory (right frontal poles, right cingulate isthmus) and sensory (right paracentral regions) function ([Fig.3a] and 3b).

Claims

Claims

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

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

3. A composition for use according to claim 1 or a kit for use according to claim 2, wherein the favorable change in EEG comprises a reduction in gamma waves in brain areas associated with executive function, language comprehension and memory processing.

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

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

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

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 the respective brain areas are reduced by 30 to 50%.

8. A composition or kit for use according to any one of claims 1 to 7, wherein the favorable change in the EEG comprises an increase in alpha 2 power in brain areas associated with working memory function and sensory functions.

9. A composition or kit for use according to claim 8, wherein the brain area associated with working memory function is the left upper zone and / or the cingulate isthmus

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

11. A composition or kit for use according to any one of claims 8 to 10, wherein alpha 2 waves expressed as relative power in the respective brain areas are increased by 20 to 40%.

12. A composition or kit for use according to any one of claims 1 to 11, wherein the treatment results in increased auditory sensory processing by neural auditory synchronization with an external auditory stimulus.

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

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

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

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

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. A composition or kit for use according to claim 17, wherein the patient is diagnosed as a patient with ASD phenotype 1 by an ASD diagnosis, and an enlarged head size at any time after birth and before 24 months of age, defined as a head circumference > 75th percentile on the CDC growth chart, a consistent worsening of ASD behavioral symptoms during episodes of immune challenges, e.g., fever, infectious events, and acute inflammation, and / or a negative reaction to a challenge test with an Nrf2 activator such as sulforaphane.

Images