Methods of treating diseases

Abstract

In one embodiment of the present invention, the present invention relates to a pharmaceutical composition for treating an individual having a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory disorders, autism spectrum disorders, and pervasive developmental disorders, the pharmaceutical composition comprising L-serine or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a method for improving or treating a disease or one or more symptoms of a disease by administering L-serine to individuals having diseases such as communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders; pharmaceutical compositions for improving or treating a disease or one or more symptoms of a disease; and the use of these for manufacturing pharmaceuticals. [Background technology]

[0002] During childhood development, from birth through infancy, childhood, and adolescence, the development of excitatory / inhibitory synapses is achieved in a balanced manner during the critical period of rebalancing in the cortical signaling pathway. This balanced synaptic development is achieved through synaptic pruning, where unused synapses are removed during the critical period, improving the efficiency of frequently used synapses. The onset and end times of synaptic pruning differ across brain regions. For example, synaptic pruning in the visual cortex begins at 8 months of age and ends at 6 years, while synaptic pruning in the prefrontal cortex begins at 2 years and ends at 11 years.

[0003] On the other hand, if synaptic pruning is not properly achieved during the critical period, neurodevelopmental disorders such as communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders may occur. Symptoms of neurodevelopmental disorders include impaired / deficit reciprocal social interaction, communication difficulties, and / or repetitive behaviors. Furthermore, early intervention should be implemented before the end of the critical period to treat or improve neurodevelopmental disorders.

[0004] However, the causes and symptoms of the above-mentioned neurodevelopmental disorders are extremely diverse, making it difficult to identify target substances and therapeutic mechanisms. Furthermore, risperidone and aripiprazole have been used to a limited extent in patients with severe aggression and severe anxiety, and they have the problem of not being able to effectively improve cognitive, social, and language development. Considering this, there is a lot of research being done on drugs / mechanisms for treating neurodevelopmental disorders. For example, drugs such as cholinergics, glutamates, intranasal oxytocin, and vasopressin 1a receptor inhibitors are being studied as drugs to treat neurodevelopmental disorders. However, these drugs have not shown a significant effect compared to placebo in patients with autism spectrum disorder, and currently there are no approved drugs or uses that enable the treatment of intersocial interaction disorders / deficiencies.

[0005] [Disclosure of the Invention] [Technical issues] There is a need for the development and therapeutic use of drugs that can improve or treat the major symptoms of patients with neurodevelopmental disorders, including autism spectrum disorder. In particular, there is a need for the development and therapeutic use of drugs that can treat intersocial interaction disorders / deficiencies.

[0006] [Solving the problem] [1] One aspect of the present invention relates to a pharmaceutical composition for treating an individual having a disorder selected from communication disorders, motor disorders, cognitive disorders, mental disorders, sensory disorders, autism spectrum disorders, and pervasive developmental disorders, comprising L-serine or a pharmaceutically acceptable salt thereof. [2] In the above [1], autism spectrum disorder may also mean childhood autism. [3] In the above [1] or [2], L-serine or a pharmaceutically acceptable salt thereof may be administered to the individual twice daily. [4] In any one of the above [1] to [3], the pharmaceutical composition may be a formulation for oral administration. [5] In any one of the above [1] to [4], the pharmaceutical composition may be a syrup formulation. [6] In any one of the above [1] to [5], the individual may be 18 years of age or younger. [7] In any one of the above [1] to [6], the individual may be 13 years old or younger, 11 years old or younger, 7 years old or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old. [8] In any one of the above [1] to [7], the weight of the individual may be between 10 and 100 kg. [9] In any one of the above [1] to [8], the weight of the individual may be between 10 and 60 kg.

[10] In any one of the above [1] to [9], the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 1 g to 60 g.

[11] In any one of the above [1] to

[10] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 30g or 2g to 28g.

[12] In any one of the above [1] to

[10] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 15g or 2g to 14g.

[13] In any one of the above [1] to

[10] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 4g to 30g or 4g to 28g.

[14] In any one of the above [1] to

[13] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 100 mg / kg to 600 mg / kg.

[15] In the above

[14] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 140 mg / kg to 580 mg / kg or 140 mg / kg to 572 mg / kg.

[16] In any one of the above [1] to

[13] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg.

[17] In any one of the above [1] to

[14] , the single dose of L-serine or a pharmaceutically acceptable salt thereof may be 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg.

[18] In any one of the above [1] to

[17] , the composition may further contain one or more of the following: sweeteners, thickeners, pH adjusters, preservatives, and solvents.

[19] Another aspect of the present invention provides a method for treating a disorder selected from communication disorders, motor disorders, cognitive disorders, mental disorders, sensory disorders, autism spectrum disorders, and pervasive developmental disorders, comprising the step of administering L-serine or a pharmaceutically acceptable salt thereof to an individual having the disorder.

[20] In the above

[19] , autism spectrum disorder may also mean childhood autism.

[21] In the foregoing

[19] or

[20] , L-serine or a pharmaceutically acceptable salt thereof may be administered to the individual twice daily.

[22] In any one of the above

[19] to

[21] , L-serine or a pharmaceutically acceptable salt thereof may be administered orally to the individual.

[23] In any one of the above

[19] to

[22] , L-serine or a pharmaceutically acceptable salt thereof may be administered to the individual as a syrup formulation.

[24] In any one of the above

[19] to

[22] , the individual may be 18 years of age or younger.

[25] In any one of the above

[19] to

[24] , the individual may be 13 years or younger, 11 years or younger, 7 years or younger, under 7 years, 2 to 7 years, or 2 to 6 years.

[26] In any one of the above

[19] to

[25] , the weight of the individual may be between 10 and 100 kg.

[27] In any one of the above

[19] to

[26] , the weight of the individual may be between 10 and 60 kg.

[28] In any one of the above

[19] to

[27] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 1 g to 60 g.

[29] In any one of the above

[19] to

[28] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 30g or 2g to 28g.

[30] In any one of the above

[19] to

[28] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 15g or 2g to 14g.

[31] In any one of the above

[19] to

[28] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 4g to 30g or 4g to 28g.

[32] In any one of the above

[19] to

[31] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 100 mg / kg to 600 mg / kg.

[33] In the above

[32] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 140 mg / kg to 580 mg / kg or 140 mg / kg to 572 mg / kg.

[34] In any one of the above

[19] to

[31] , the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg.

[35] In any one of the above

[19] to

[31] , the single dose of L-serine or a pharmaceutically acceptable salt thereof may be 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg.

[36] Yet another aspect of the present invention relates to the use of the pharmaceutical compositions described in [1] to

[18] above for manufacturing pharmaceuticals for improving, preventing or treating disorders selected from communication disorders, motor disorders, cognitive disorders, mental disorders, sensory disorders, autism spectrum disorders, and pervasive developmental disorders.

[0007] [Advantageous effects of the invention] In one embodiment of the present invention, communication, daily living skills, socialization, motor skills, maladaptive behaviors, and overall clinical impression severity in patients were improved by oral administration of L-serine to patients with autism spectrum disorder, and early initiation of L-serine administration (e.g., under or before 7 years of age) resulted in better improvements in communication, daily living skills, socialization and motor skills, maladaptive behaviors, and parental stress in patients. [Brief explanation of the drawing]

[0008] [Figure 1] This document outlines the social skills experiment and the social cognition experiment in the autism spectrum disorder model, as well as figures showing the results of the social skills and social cognition experiments. Figure 1A shows an outline of the social skills experiment, and Figure 1B shows an outline of the social cognition experiment. Figures 1C and 1D show the results of the social skills experiment. Figures 1E and 1F show the results of the social cognition experiment. In Figure 1, * indicates a p-value < 0.05, ** indicates a p-value < 0.01, *** indicates a p-value < 0.001, **** indicates a p-value < 0.0001, and ns indicates that the result is not statistically significant. [Figure 2] Figures 2A and 2D show the elevated cross maze used in anxiety experiments in an autism spectrum disorder model, the results of the anxiety experiments, and the results of the anxiety experiments. Figure 2A is a schematic diagram of the elevated cross maze used in anxiety experiments in an autism spectrum disorder model, Figure 2B is a schematic diagram of a heat map tracking the movement of mice during behavioral tests, and Figures 2C and 2D show the results of the anxiety experiments, respectively. In Figure 2, * indicates a p-value < 0.05, ** indicates a p-value < 0.01, *** indicates a p-value < 0.001, and ns indicates that the result is not statistically significant. [Figure 3]Figure showing the experimental results obtained by confirming the normalization effect of dopamine secretion in an autism spectrum disorder model using patch clamp. A in Fig. 3 is a figure showing the analysis results of the firing rate of spontaneous action potentials in the midbrain VTA region in the control group and each experimental group, and B in Fig. 3 is a figure showing the analysis results of the potential frequency in the control group and each experimental group. In Fig. 3, * indicates p < 0.05, and ** indicates p < 0.01. [Figure 4] Figure showing the results obtained by conducting an experiment to confirm the effect of normalizing synaptic pruning in an autism spectrum disorder model. A in Fig. 4 is a figure obtained by observing the prelimbic cortex as a whole, B in Fig. 4 is a figure obtained by observing the distribution of dendritic spine density of cortical layer 5 pyramidal neurons using a confocal microscope system, and C in Fig. 4 is a figure showing the dendritic spine density of cortical layer 5 pyramidal neurons between each group. In Fig. 4, ** indicates p < 0.01, and **** indicates p < 0.0001. [Figure 5] Figure showing the experimental results obtained by confirming the intrinsic excitability of mPFC pyramidal neurons in an autism spectrum disorder model using patch clamp. A in Fig. 5 is a figure showing the firing rate of action potentials by current injection, and B in Fig. 5 is a figure showing the change in the firing rate in Fig. 8A. In Fig. 5, ** indicates p < 0.01, *** indicates p < 0.001, and **** indicates p < 0.0001. [Figure 6] Figure showing the differences in spatial working memory for each L - serine dosage in an autism spectrum disorder model. [Figure 7] Figure showing the differences in individual recognition for each L - serine dosage in an autism spectrum disorder model. [Figure 8] Figure showing the plasma concentration - time profile of beagle dogs administered L - serine orally or intravenously. [Figure 9] Figure showing the outline of the phase 2 clinical trial. [Figure 10]This figure shows the trends (line plots) for three groups at 12, 24, and 36 weeks after the start of the Phase 2 clinical trial, in relation to the change in score at the start of the trial. [Figure 11] This figure (forest plot) shows the difference in efficacy between the treatment groups (high-dose and low-dose groups) compared to the control group (placebo) (within the FAS population) at 12 weeks after administration of AST-001 syrup, along with 90% confidence intervals and statistical significance, for the K-VABS-II ABC, main domain, and parental distress scores measured by the Korean-Parenting Stress Index-4th ​​Edition Short Form (hereinafter referred to as K-PSI-4-SF) in relation to the difference in efficacy at the start of the Phase 2 clinical trial. [Figure 12] This figure was obtained by analyzing the change in K-VABS-II 2-Domain Composite (the mean of both communication and social scores, hereinafter referred to as 2DC) scores at 12, 24, and 36 weeks after the start of the Phase 2 clinical trial, relative to the change in scores at the start of the trial (within the FAS population). [Figure 13] This figure shows the trends (line plots) for the change in Clinical Overall Impression Severity (CGI-S) score (hereinafter referred to as CGI-S) at 2, 4, 8, 12, 14, 16, 24, and 36 weeks (within the FAS population) for each of the three groups at each time point, relative to the score change at the start of the Phase 2 clinical trial. [Figure 14] This figure was obtained by analyzing the change in K-VABS-II ABC at 12, 24, and 36 weeks (within the PPS population) relative to the change at the start of the Phase 2 clinical trial. [Figure 15] This figure shows an overview of a clinical trial involving continuous administration for 52 weeks. [Figure 16]This figure shows the trends (line plots) in the CGI-S scores (within the FAS population) of two groups at each time point from the start of the Phase 2 clinical trial to the completion of the 52-week continuous administration clinical trial in patients who participated in the trial. [Figure 17] This figure shows the trend (line plot) of the change in CGI-S score (within the FAS population) for two groups at each time point from the start of the Phase 2 clinical trial to the completion of the 52-week continuous administration clinical trial in patients who participated in the trial. [Figure 18] This figure shows the results obtained by predicting the pattern of K-VABS-II ABC scores when AST-001 is administered for 12 weeks in a simulation analysis for dosage modeling used in Phase 3 clinical trials. [Modes for carrying out the invention]

[0009] L-serine or a pharmaceutically acceptable salt thereof The L-serine used in this invention is the compound shown in the following chemical formula 1. [Chemical formula 1] [ka]

[0010] Pharmacologically acceptable salts of L-serine are those commonly used in the pharmaceutical industry and may include inorganic salts, inorganic acid salts, organic acid salts, and sulfonates.

[0011] Target diseases for treatment or symptom improvement In one aspect of the present invention, the target disease to be treated or improved by administering L-serine or a pharmaceutically acceptable salt thereof may be a disease selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders.

[0012] Treatment of a disease may include alleviating the symptoms of the disease or preventing the disease.

[0013] Communication disorders are conditions that impair communication abilities and can manifest in various conditions such as neurological disorders (e.g., traumatic brain injury), mental disorders (e.g., panic disorder, post-traumatic stress disorder), autism spectrum disorder, and language disorders.

[0014] Motor skill disorders are caused by problems with the ability to move the body and can occur in a variety of conditions, including neurological disorders, mental disorders, and autism spectrum disorder.

[0015] Cognitive impairment is a problem with the cognitive ability to recognize surrounding objects, people, or the environment, and can manifest as neurological disorders, psychiatric disorders, or autism spectrum disorders.

[0016] A mental disorder is a psychological health problem that persistently interferes with or limits normal thinking, feeling, behavior, or social relationships, and can manifest as depression, bipolar disorder, panic disorder, sadness, schizophrenia, neurosis, obsessive-compulsive disorder, post-traumatic stress disorder, and cognitive impairment.

[0017] Sensory impairments result from abnormalities in the perception of external stimuli and can manifest as neurological disorders, mental disorders, or autism spectrum disorders.

[0018] Pervasive developmental disorders include delays in an individual's abilities that should develop normally during physical and mental development, such as motor skills, cognitive abilities, and sensory abilities.

[0019] Autism spectrum disorder is known as a neurodevelopmental disorder syndrome characterized by anxiety as well as core symptoms such as difficulties in social interaction. Non-limited examples of autism spectrum disorder include, but are not limited to, autism spectrum disorder, childhood autism, a wide range of developmental disorders and disorders including Asperger's syndrome, Angelman syndrome, fragile X syndrome, fragile X-related tremor / ataxia syndrome (FXTAS), Rett syndrome, Landau-Klefner syndrome, Prader-Willi syndrome, tardive dyskinesia, and Williams syndrome.

[0020] Furthermore, individuals with autism spectrum disorder may meet the requirements for autism spectrum disorder as defined by the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision) and / or the Autism Diagnostic Interview-Revised (ADI-R).

[0021] Pharmaceutical composition and its use One aspect of the present invention relates to a pharmaceutical composition for treating individuals having a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders, the pharmaceutical composition comprising L-serine or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment of the present invention, autism spectrum disorder may be childhood autism. Childhood autism is a disease classified under Korean Classification of Disease Code F84.0 or International Classification of Disease (ICD) F84.0.

[0023] In another embodiment of the present invention, L-serine or a pharmaceutically acceptable salt thereof may be administered to a subject more than once daily, once, twice, three, four, or five times daily; however, administration twice daily is preferred.

[0024] In yet another embodiment of the present invention, the pharmaceutical composition may be a parenteral formulation or an oral formulation, and preferably an oral formulation. The pharmaceutical composition according to the present invention may be formulated by mixing with pharmaceutically acceptable excipients.

[0025] In one embodiment of the present invention, the pharmaceutical composition may be a syrup formulation.

[0026] In another embodiment of the present invention, the subject may be an adult, or may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old, preferably 18 years or younger, 13 years or younger, 11 years or younger, 7 years or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old. Furthermore, the individual may be a child, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old, or 18 years or younger, 13 years or younger, 11 years or younger, 7 years or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old.

[0027] In yet another embodiment of the present invention, the weight of the subject may be 10-100 kg, 10-90 kg, 10-80 kg, 10-70 kg, or 10-60 kg.

[0028] In one embodiment of the present invention, the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 12g, 13g, 14g, 15g, 16g, 17g, 18g, 19g, 20g, 21g, 22g, 23g, 24g, 25g, 26g, 27g, 28g, 29g, 30g, 31g, 32g, 33g, 34g, 35g, 36g, 37g, 38g, 39g, 40g, 41g, 42g, 43g, 44g, 45g, 46g, 47g, 48g, 49g, 50g, 51g, 52g, 53g, 54g, 5 It may be one or more selected from the group consisting of 5g, 56g, 57g, 58g, 59g, 60g, 61g, 62g, 63g, 64g, 65g, 66g, 67g, 68g, 69g, 70g, 71g, 72g, 73g, 74g, 75g, 76g, 77g, 78g, 79g, 80g, 81g, 82g, 83g, 84g, 85g, 86g, 87g, 88g, 89g, 90g, 91g, 92g, 93g, 94g, 95g, 96g, 97g, 98g, 99g, and 100g, or it may be 1g-60g, 2g-30g, 2g-28g, or 4g-28g. Furthermore, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g, 4g, 7g, 8g, 10g, 12g, 14g, 20g, or 28g depending on the body weight of the individual, and the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be the daily doses for each body weight listed in Tables 4 and 15.

[0029] In another embodiment of the present invention, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 15g or 2g to 14g, or 4g to 30g or 4g to 28g.

[0030] In another embodiment of the present invention, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 100 mg / kg to 600 mg / kg, 140 mg / kg to 580 mg / kg, 140 mg / kg to 572 mg / kg, 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg. Furthermore, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 180 mg / kg, 300 mg / kg, 480 mg / kg, or 600 mg / kg. Furthermore, the total daily dose of L-serine or its pharmaceutically acceptable salt is approximately 285.7–400 mg / kg, 333.3–533.3 mg / kg, 378.4–560 mg / kg, 392.2–526.3 mg / kg, 466.7–538.5 mg / kg, 142.9–200 mg / kg, and 166.7– It may also be approximately 266.7 mg / kg, approximately 189.2 to approximately 280 mg / kg, approximately 196.1 to approximately 263.2 mg / kg, approximately 233.3 to approximately 269.2 mg / kg, or approximately 200 mg / kg to approximately 400 mg / kg, approximately 285 to approximately 400 mg / kg, approximately 333 to approximately 534 mg / kg, approximately 378 to approximately 560 mg / kg, approximately 392 to approximately 527 mg / kg, approximately 4 The daily dose may be 66-539 mg / kg, 142-200 mg / kg, 166-267 mg / kg, 189-280 mg / kg, 196-264 mg / kg, 233-270 mg / kg, 200 mg / kg-400 mg / kg, or 307.7-400 mg / kg, or 400 mg / kg-571.4 mg / kg, 352.9 mg / kg-571.4 mg / kg, 408.2 mg / kg-571.4 mg / kg, 280 mg / kg, 311.1 mg / kg, 350 mg / kg, 400 mg / kg, 466.7 mg / kg, or 560 mg / kg, as listed in Tables 4 and 15 for each body weight.

[0031] In another embodiment of the present invention, the single dose of L-serine or a pharmaceutically acceptable salt thereof may be 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg. Furthermore, the single dose of L-serine or a pharmaceutically acceptable salt may be approximately 142.9–200 mg / kg, approximately 166.7–266.7 mg / kg, approximately 189.2–280 mg / kg, approximately 196.1–263.2 mg / kg, approximately 233.3–269.2 mg / kg, approximately 71.4–100 mg / kg, approximately 83.3–133.3 mg / kg, approximately 94.6–140 mg / kg, approximately 98–131.6 mg / kg, or approximately 116.7–134.6 mg / kg, or approximately 142–200 mg / kg, approximately 166–267 mg / kg, approximately 189–280 mg / kg, or approximately 196–26 The dose may be 4 mg / kg, approximately 233–270 mg / kg, approximately 71–100 mg / kg, approximately 83–134 mg / kg, approximately 94–140 mg / kg, approximately 98–132 mg / kg, approximately 116–135 mg / kg, approximately 153.8–200 mg / kg, approximately 200–285.7 mg / kg, approximately 176.5–285.7 mg / kg, approximately 204.1–285.7 mg / kg, approximately 140 mg / kg, approximately 155.6 mg / kg, approximately 175 mg / kg, approximately 200 mg / kg, approximately 233.3 mg / kg, or approximately 280 mg / kg, and may also be a single dose for each body weight listed in Tables 4 and 15.

[0032] In one embodiment of the present invention, the pharmaceutical composition may contain one or more of the following: sweeteners, thickeners, pH adjusters, solvents, and preservatives.

[0033] The substance used as a sweetener may be any substance used in the art to which the present invention pertains to improve the taste, stability, or miscibility of a pharmaceutical composition. The sweeteners used may include, but are not limited to, sorbitol, maltodextrin, fructose, glycerin, propylene glycol, peanut oil, sorbitan, stevia, and sucralose. Preferably, one or more sweeteners selected from sucralose, sorbitol, acesulfame, and sucralose may be used.

[0034] The substance used as a thickening agent may be any substance used in the art to which the present invention pertains to improve the stability and consistency of a pharmaceutical composition. The thickening agents used may include, but are not limited to, carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone, polyethylene oxide, gum arabic, sorbitol, and polysorbate; however, carboxymethylcellulose may be used, and is preferred.

[0035] The substance used as a pH adjuster may be any substance used to adjust the pH of a pharmaceutical composition in the art to which the present invention pertains. The pH adjuster used may be a basic pH adjuster, an acidic pH adjuster, a phosphate buffer, sodium bicarbonate, an ammonia solution, sodium chloride, etc.; however, it is not limited thereto, and preferably an acidic pH adjuster, more preferably citric acid (e.g., citric acid hydrate, potassium citrate monohydrate) may be used.

[0036] The substance used as a preservative may be any substance used in the art to which the present invention pertains to maintain the stability and efficacy of a pharmaceutical composition. The preservative used may be sodium benzoate, benzyl alcohol, parabens, formaldehyde, etc., with methyl parahydroxybenzoate and / or propyl parahydroxybenzoate being preferred.

[0037] The solvent contained in the pharmaceutical composition is a solvent commonly used in the art to which the present invention belongs, and may include purified water, alcohol solvents, acetone, etc., with purified water being preferred.

[0038] In one embodiment of the present invention, the pharmaceutical composition may comprise carboxymethylcellulose, citric acid, a sweetener, and purified water, the sweetener may be a combination of sucrose and sorbitol, or a combination of sucralose and acesulfame, and the pharmaceutical composition may further comprise methyl parahydroxybenzoate and / or propyl parahydroxybenzoate.

[0039] In yet another embodiment of the present invention, the pharmaceutical composition may contain one or more of the following: sweeteners, thickeners, pH adjusters, solvents, preservatives, and flavoring agents. The substance used as the flavoring agent may be any substance used in the art to which the present invention belongs to impart a fragrance to a pharmaceutical composition or to improve the user experience. The flavoring agent used may be peppermint oil, lemon essential oil, vanilla extract, spices, etc.

[0040] A further aspect of the present invention relates to the use of the above-described pharmaceutical composition for manufacturing a medicament for improving, preventing or treating a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders.

[0041] Treatment method One aspect of the present invention relates to a method for treating a disorder selected from communication disorders, motor disorders, cognitive disorders, mental disorders, sensory disorders, autism spectrum disorders, and pervasive developmental disorders, comprising the step of administering L-serine or a pharmaceutically acceptable salt thereof to an individual having the disorder.

[0042] In one embodiment of the method for treating the disease of the present invention, the autism spectrum disorder may be childhood autism. Childhood autism is a disease name classified under Korean Classification of Disease Code F84.0 or International Classification of Disease (ICD) F84.0.

[0043] In another embodiment of the method for treating the disease of the present invention, L-serine or a pharmaceutically acceptable salt thereof may be administered to a subject more than once daily, once, twice, three, four, or five times daily; however, administration twice daily is preferred.

[0044] In yet another embodiment of the method for treating a disease according to the present invention, L-serine or a pharmaceutically acceptable salt thereof may be administered orally to an individual. Furthermore, L-serine or a pharmaceutically acceptable salt thereof may be administered to an individual as a syrup formulation. Furthermore, for the individual, L-serine or a pharmaceutically acceptable salt thereof may be formulated into the above-mentioned oral administration formulation.

[0045] In one embodiment of the method for treating the disease of the present invention, the subject may be an adult, or may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old, preferably 18 years old or younger, 13 years old or younger, 11 years old or younger, 7 years old or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old. Furthermore, the individual may be a child, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years old, or 18 years old or younger, 13 years old or younger, 11 years old or younger, 7 years old or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old.

[0046] In another embodiment of the method for treating the disease of the present invention, the weight of the subject may be 10-100 kg, 10-90 kg, 10-80 kg, 10-70 kg, or 10-60 kg.

[0047] In one embodiment of the method for treating the disease of the present invention, the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 12g, 13g, 14g, 15g, 16g, 17g, 18g, 19g, 20g, 21g, 22g, 23g, 24g, 25g, 26g, 27g, 28g, 29g, 30g, 31g, 32g, 33g, 34g, 35g, 36g, 37g, 38g, 39g, 40g, 41g, 42g, 43g, 44g, 45g, 46g, 47g, 48g, 49g, 50g, 51g, 52g, 53g, It may be one or more selected from the group consisting of 54g, 55g, 56g, 57g, 58g, 59g, 60g, 61g, 62g, 63g, 64g, 65g, 66g, 67g, 68g, 69g, 70g, 71g, 72g, 73g, 74g, 75g, 76g, 77g, 78g, 79g, 80g, 81g, 82g, 83g, 84g, 85g, 86g, 87g, 88g, 89g, 90g, 91g, 92g, 93g, 94g, 95g, 96g, 97g, 98g, 99g, and 100g, or it may be 1g-60g, 2g-30g, 2g-28g, or 4g-28g. Furthermore, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g, 4g, 7g, 8g, 10g, 12g, 14g, 20g, or 28g depending on the body weight of the individual, and the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be the daily doses for each body weight listed in Tables 4 and 15.

[0048] In yet another embodiment of the method for treating the disease of the present invention, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 2g to 15g or 2g to 14g, or 4g to 30g or 4g to 28g.

[0049] In another embodiment of the method for treating the disease of the present invention, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 100 mg / kg to 600 mg / kg, 140 mg / kg to 580 mg / kg, 140 mg / kg to 572 mg / kg, 140 mg / kg to 580 mg / kg, or 140 mg / kg to 572 mg / kg. Furthermore, the daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 180 mg / kg, 300 mg / kg, 480 mg / kg, or 600 mg / kg. Furthermore, the total daily dose of L-serine or its pharmaceutically acceptable salt is approximately 285.7–400 mg / kg, 333.3–533.3 mg / kg, 378.4–560 mg / kg, 392.2–526.3 mg / kg, 466.7–538.5 mg / kg, 142.9–200 mg / kg, and 166.7– It may also be approximately 266.7 mg / kg, approximately 189.2 to approximately 280 mg / kg, approximately 196.1 to approximately 263.2 mg / kg, approximately 233.3 to approximately 269.2 mg / kg, or approximately 200 mg / kg to approximately 400 mg / kg, approximately 285 to approximately 400 mg / kg, approximately 333 to approximately 534 mg / kg, approximately 378 to approximately 560 mg / kg, approximately 392 to approximately 527 mg / kg, approximately 4 The daily dose may be 66-539 mg / kg, 142-200 mg / kg, 166-267 mg / kg, 189-280 mg / kg, 196-264 mg / kg, 233-270 mg / kg, 200 mg / kg-400 mg / kg, or 307.7-400 mg / kg, or 400 mg / kg-571.4 mg / kg, 352.9 mg / kg-571.4 mg / kg, 408.2 mg / kg-571.4 mg / kg, 280 mg / kg, 311.1 mg / kg, 350 mg / kg, 400 mg / kg, 466.7 mg / kg, or 560 mg / kg, as listed in Tables 4 and 15 for each body weight.

[0050] In one embodiment of the method for treating the disease of the present invention, the total daily dose of L-serine or a pharmaceutically acceptable salt thereof may be 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg.

[0051] In yet another embodiment of the method for treating the disease of the present invention, the single dose of L-serine or a pharmaceutically acceptable salt thereof may be 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg. Furthermore, the single dose of L-serine or a pharmaceutically acceptable salt may be approximately 142.9–200 mg / kg, approximately 166.7–266.7 mg / kg, approximately 189.2–280 mg / kg, approximately 196.1–263.2 mg / kg, approximately 233.3–269.2 mg / kg, approximately 71.4–100 mg / kg, approximately 83.3–133.3 mg / kg, approximately 94.6–140 mg / kg, approximately 98–131.6 mg / kg, or approximately 116.7–134.6 mg / kg, or approximately 142–200 mg / kg, approximately 166–267 mg / kg, approximately 189–280 mg / kg, or approximately 196–26 The dose may be 4 mg / kg, approximately 233–270 mg / kg, approximately 71–100 mg / kg, approximately 83–134 mg / kg, approximately 94–140 mg / kg, approximately 98–132 mg / kg, approximately 116–135 mg / kg, approximately 153.8–200 mg / kg, approximately 200–285.7 mg / kg, approximately 176.5–285.7 mg / kg, approximately 204.1–285.7 mg / kg, approximately 140 mg / kg, approximately 155.6 mg / kg, approximately 175 mg / kg, approximately 200 mg / kg, approximately 233.3 mg / kg, or approximately 280 mg / kg, and may also be a single dose for each body weight listed in Tables 4 and 15.

[0052] The present invention will be described in more detail below with reference to the following examples. However, the following examples are illustrative for explaining the present invention and do not limit the scope of the present invention to them.

[0053] Example 1. In vivo experiment using an animal model of autism spectrum disorder. Example 1.1. Effects on improving social skills, social cognition, and anxiety. Pregnant C57BL / 6 mice were subcutaneously injected with valproic acid (VPA) when the gestation period reached 12 days. Male mice were selected from those born to these VPA-injected pregnant mice and used as a mouse model for autism spectrum disorder.

[0054] Since 3-week-old mice are in a critical period, normal 3-week-old mice and 3-week-old mice with autism spectrum disorder were subjected to social behavior experiments, social cognition experiments, and anxiety experiments to identify underlying characteristics. Mice in which underlying characteristics of autism spectrum disorder were confirmed were orally administered 500 mg / kg of L-serine (hereinafter referred to as AST-001) for 2 weeks. Social behavior experiments, social cognition experiments, and anxiety experiments were repeated for the AST-001 orally administered 2-week-old mice with autism spectrum disorder.

[0055] Social Experiment A behavioral experiment was conducted to determine whether experimental mice would move towards a social object (an unfamiliar mouse) and an unsocial object (an empty cage) when these objects were placed in the rooms on either side of a three-room structure (see Figure 1A). For two weeks starting at three weeks of age, the normal group and the autism spectrum disorder group were orally administered water once daily. In the drug group, mice with autism spectrum disorder were orally administered 500 mg / kg of AST-001 (dissolved in water) once daily. Five-week-old normal mice (n=6) and five-week-old mice with autism spectrum disorder (n=6) were used in the experiment. Five-week-old normal mice showed a social preference index, moving towards the social object, while five-week-old mice with autism spectrum disorder did not. However, behavioral experiments in a group orally administered AST-001 for two weeks confirmed that mice with autism spectrum disorder had a higher social preference index for social objects (see Figure 1C and Figure 1D). Specifically, in mice with autism spectrum disorder that were not administered AST-001, there was no significant difference between the time spent interacting with social objects and the time spent interacting with empty cages, and the difference was not statistically significant, indicating a low preference index for social objects (see Figure 1C and Figure 1D). On the other hand, in the control group and mice with autism spectrum disorder administered 500 mg / kg of AST-001, the time spent interacting with social objects was significantly higher than the time spent interacting with empty cages, and the difference was statistically significant, indicating a high preference index for social objects (see Figure 1C and Figure 1D).

[0056] Social Cognitive Experiments A social cognition experiment was conducted to measure whether experimental mice would move towards unfamiliar mice when placed between unfamiliar and familiar mice (see Figure 1B). For two weeks starting at 3 weeks of age, the normal group and the autism spectrum disorder group were orally administered water once daily. In the drug group, mice with autism spectrum disorder were orally administered 500 mg / kg of AST-001 (dissolved in water) once daily. Five-week-old normal mice (n=6) and five-week-old mice with autism spectrum disorder (n=6) were used in the experiment. It was found that five-week-old normal mice moved more favorably towards unfamiliar mice, while five-week-old mice with autism spectrum disorder did not show a preference index towards unfamiliar mice. However, in social cognition experiments with the group orally administered AST-001 for two weeks, mice with autism spectrum disorder showed an increased preference index for unfamiliar mice (see Figure 1E and Figure 1F). Specifically, in mice with autism spectrum disorder not administered AST-001, there was no significant difference between the time spent interacting with familiar mice and the time spent interacting with unfamiliar mice; the difference was not statistically significant, and the preference index for unfamiliar mice was low (see Figure 1E and Figure 1F). On the other hand, in the control group and mice with autism spectrum disorder administered 500 mg / kg of AST-001, the time spent interacting with unfamiliar mice was significantly higher than the time spent interacting with familiar mice; the difference was statistically significant, and the preference index for unfamiliar mice was high (see Figure 1E and Figure 1F). In other words, oral administration of AST-001 was confirmed to improve social cognition in mice with autism spectrum disorder.

[0057] Anxiety experiment An anxiety experiment was conducted to test whether experimental mice exhibited anxious behavior to avoid the open-arm space when placed in an elevated cross maze device (see Figure 2A). For two weeks starting at 3 weeks of age, the normal group and the autism spectrum disorder group were orally administered water once daily. In the drug group, mice with autism spectrum disorder were orally administered 500 mg / kg of AST-001 (dissolved in water) once daily. Five-week-old normal mice (n=6) and five-week-old mice with autism spectrum disorder (n=6) were used in the experiment. Five-week-old mice with autism spectrum disorder showed a tendency to avoid the open-arm space compared to five-week-old normal mice. However, in the anxiety experiment with the group that received oral AST-001 for two weeks, the mice with autism spectrum disorder showed a reduced level of anxiety and spent more time going to the open-arm space (see Figures 2B to 2D). Specifically, mice with autism spectrum disorder that were not administered AST-001 spent very little time in the open-arm space of the elevated cross maze and a long time in the closed-arm space (see Figure 2C and Figure 2D). However, mice with autism spectrum disorder that were administered 500 mg / kg of AST-001 spent significantly more time in the open-arm space of the elevated cross maze and shorter time in the closed-arm space compared to mice with autism spectrum disorder that were not administered AST-001 (see Figure 2C and Figure 2D). As a result, oral administration of AST-001 was confirmed to improve the level of anxiety in mice with autism spectrum disorder.

[0058] Examples 1 and 2: Effect of normalizing dopamine secretion A mouse model of autism spectrum disorder was created using the method described in Example 1.1. Three-week-old male mice with autism spectrum disorder were divided into two groups: one group (n=6) orally administered 250 mg / kg of AST-001 for two weeks, and the other group (n=6) orally administered 500 mg / kg of AST-001 for two weeks. Both groups were then orally administered AST-001. The three-week-old male normal mouse group and the autism spectrum disorder mouse group (n=6) were orally administered water once daily for two weeks, after which they served as the control group (n=6) in behavioral experiments.

[0059] Spontaneous action potentials of dopamine neurons in the midbrain VTA region of 5-week-old normal mice and 5-week-old mice with autism spectrum disorder were examined using patch-clamp analysis. It was found that mice with autism spectrum disorder had a reduced firing rate of spontaneous action potentials compared to normal mice (see Figure 3A). As a result, dopamine secretion was reduced in mice with autism spectrum disorder, and this reduced dopamine secretion is causing behavioral abnormalities related to dopamine pathways such as attention, reward, and cognition.

[0060] However, after oral administration of AST-001 for two weeks, the firing rate of spontaneous action potentials in mice with autism spectrum disorder was found to be similar to that of normal mice (Figure 3A and Figure 3B). As a result, it was confirmed that administration of AST-001 at doses of 250 mg / kg to 500 mg / kg increased dopamine secretion in mice with autism spectrum disorder.

[0061] Example 1.3. Effect of normalizing synaptic pruning A mouse model of autism spectrum disorder was created using the method described in Example 1.1. In autism spectrum disorder, it is known that the number of dendrites increases excessively due to impaired synaptic pruning during the critical period. Therefore, an experiment was conducted to confirm whether the number of dendrites could be normalized by administering AST-001. For reference, the results obtained by observing the anterior limbic cortex with a confocal microscope system are shown in Figure 4A.

[0062] Eight three-week-old male mice with autism spectrum disorder (n=8) were orally administered 400 mg / kg of AST-001 for two weeks. The spine density of synaptic dendrites was then examined to determine if it was similar to that of three normal male control mice (n=3). The number of dendrites in mice with autism spectrum disorder was significantly reduced and was found to be similar to that of the control group (see Figures 4B and 4C). These results confirmed that oral administration of AST-001 normalizes synaptic pruning during the critical period of autism spectrum disorder.

[0063] Example 1.4. Effect of normalizing nerve cell activity We purchased BTBR T+tf / J (BTBR) and C57BL / 6 mice (used as a control group), animals with autism spectrum disorder, from Jackson Laboratories. When the intrinsic excitability of mPFC pyramidal neurons in 3-week-old BTBR mice (n=3) and C57BL / 6 mice (n=3) was measured by the firing rate of action potentials induced by current injection using patch clamp, the firing rate of action potentials was reduced in BTBR mice compared to the control group (see Figure 5A). However, when the firing rate of action potentials was measured after orally administering 500 mg / kg of AST-001 to BTBR mice for 2 weeks, it was found that the firing rates of action potentials in BTBR mice and control mice were similar (see Figure 5B).

[0064] Example 1.5. Effect of improving individual recognition and spatial memory Individual Recognition Experiment Autism spectrum disorder mice were prepared using the same method as in Example 1.1. Three-week-old male mice with autism spectrum disorder were orally administered 180, 300, 480, or 600 mg / kg / day of L-serine for 21 days, followed by individual recognition testing. Eight mice were used in each experimental group.

[0065] Mice tend to be more interested in novel objects than familiar ones. Therefore, we conducted a novel object recognition (NOR) experiment to determine whether or not mice recognize novel objects.

[0066] As the dose of AST-001 increased, the discriminant index (DI), which indicates the degree to which mice with autism spectrum disorder recognized and remembered novel objects, also increased (see Figure 6).

[0067] Spatial memory experiment Autism spectrum disorder mice were prepared using the same method as in Example 1.1. Three-week-old male mice with autism spectrum disorder were orally administered 180, 300, 480, or 600 mg / kg of L-serine for 28 days, followed by a spatial memory test. Normal mice were used as a control group. Eight mice were used in each experimental group.

[0068] The spatial working memory of mice was evaluated using a Y-maze test. As the dose of L-serine increased, the value of spontaneous change, a measure of spatial memory, increased (see Figure 7).

[0069] Example 2. Pharmacokinetic experiment Example 2.1. Pharmacokinetic experiments in Beagle dogs Beagle dogs (1.8–2.6 years old, 8.6–11.6 kg, n=20) were administered 4 g or 8 g of L-serine orally or intravenously. Blood samples were taken separately: a basal blood sample taken before L-serine administration and a primary blood sample taken after administration. The beagle dogs were kept fasted throughout the experiment, and plasma L-serine concentrations were analyzed by LC-MS / MS.

[0070] The plasma concentration-time profiles after oral or intravenous administration of L-serine in Beagle dogs are shown in Figure 8.

[0071] Area under the plasma concentration-time curve (AUC) calculated from the time-course plasma drug concentration curves after oral administration of 4 g or 8 g of L-serine. inf The drug loss half-life (t) was 627.7±108.4 μg·hr / mL and 1,329.0±317.8 μg·hr / mL, respectively. 1 / 2The estimated response times were 3.8 ± 1.4 hours and 4.7 ± 1.8 hours, respectively. Bioavailability after oral administration was 106.5% and 84.2% per individual after administration of 4 g and 8 g, respectively.

[0072] Example 2.2. Pharmacokinetic experiments in adult males Healthy adult males were subjected to pharmacokinetic experiments according to the experimental design shown in Table 1 below. Blood samples were collected 24 hours before administration of AST-001 (active ingredient L-serine), and the L-serine concentration was measured. 60g of AST-001 powder was a uniform white powder free of foreign matter, divided and repackaged in HDPE bottles or bottles made of the same material, and the composition of this drug was such that each 1,000mg dose contained 1,000mg of the active ingredient L-serine.

[0073] [Table 1]

[0074] 24 hours prior to AST-001 administration, overall, basal L-serine levels did not show a pattern of change over time from baseline L-serine, and no trend was observed over the course of a day. Cmax and AUC after systemic exposure to L-serine. last AUC inf The accumulation rate showed a linear increase with increasing doses of AST-001 after a single oral administration of 10g, 15g, 20g, or 30g of AST-001. On the other hand, AST-001 reached a steady state after repeated oral administration of 15g twice daily for 7 days, and its average half-life was found to be approximately 11 hours. At steady state, the average accumulation index was approximately 1.7 times that of a single 15g dose of AST-001.

[0075] As a result of summarizing the safety evaluation from adverse events, clinical examinations, vital signs, electrocardiograms, physical examinations, etc., AST-001 showed excellent safety and drug tolerance in healthy adults when administered orally once a day up to 30 g per day, or when administered orally at 15 g twice a day for 7 days repeatedly. As a result, it was confirmed that AST-001 can be safely administered in a dosage range of 10 - 30 g per day for indications that require repeated dosing.

[0076] The results of the pharmacokinetic analysis in the repeated-dose study of AST-001 in healthy adult males are as shown in Table 2 below.

[0077]

Table 2

[0078] Example 2.3. Population Pharmacokinetic Simulation Applying zero-order absorption with first-order elimination to a two-compartment model, a population pharmacokinetic model of AST-001 was constructed, and a proportional error model was used for the residual model. In the case of baseline L-serine, it was further reflected in the model in the form of injecting L-serine at steady state. The following pharmacokinetic parameters were reflected in the model by applying allometric scaling to body weight. V1 = V1×(body weight / 70)^1 V2 = V2×(body weight / 70)^1 Q = Q×(body weight / 70)^0.75 CL = CL×(body weight / 70)^0.75

[0079] AUC at steady state after administration by 15 g BID regimen in healthy adults tauThe target exposure was approximately 882.8 h*μg / mL. The NONMEM version 7.4 program was used for population pharmacokinetic simulation analysis, and blood sampling time and L-serine blood concentration data were analyzed using the FOCE INTERACTION option.

[0080] Furthermore, overall, the analytical results did not show a pattern of change over time in baseline L-serine, and baseline L-serine was consistently detected within the concentration range of 5–30 μg / mL. The mean AUC of L-serine without baseline correction was measured after single doses of 10g, 20g, and 30g of AST-001. last The mean AUC values ​​for L-serine, uncorrected for baseline, were 613.3 h*μg / mL, 1,134.6 h*μg / mL, and 1,525.5 h*μg / mL, respectively, when 15 g of AST-001 was administered twice daily for one week. tau The concentration was 882.8 h*μg / mL. The mean half-life of L-serine administered extracorporeally using AST-001 was 6.5 to 14.0 hours.

[0081] When simulating the dosage and administration for each weight range, the exposure at the recommended dosage of 400 mg / kg or 100 mg / kg corresponds to the target AUC. tau The difference was within 30%. Considering the drug exposure observed in clinical trials conducted in healthy adults, it was analyzed that AST-001 doses of 4g / day to 28g / day and AST-001 doses of 400mg / kg / day showed similar effects in children (see Table 3).

[0082] [Table 3]

[0083] Example 3. Phase 2 Clinical Trial Fifty-one children with autism spectrum disorder were included in a multicenter, randomized, double-blind, placebo-controlled Phase 2 clinical trial to investigate the efficacy and evaluate the safety of AST-001 syrup. A summary of the Phase 2 clinical trial is shown in Figure 9.

[0084] The AST-001 syrup used in clinical trials is an aromatic, sweet, colorless or pale yellow, transparent syrup containing 10 g of L-serine as its main component in approximately 100 mL of this drug, packaged in aluminum foil in doses of 2 g / 20 mL. The composition of AST-001 syrup is as follows: L-serine as the main component, sodium carboxymethylcellulose as a thickener, methyl parahydroxybenzoate and propyl parahydroxybenzoate as preservatives, citric acid hydrate and potassium citrate hydrate as pH adjusters, sucrose and D-sorbitol solution as sweeteners, apple mint flavoring SJ-G (22005221) as a flavoring agent, and purified water. A syrup with the same appearance was used as a placebo. AST-001 syrup-placebo is manufactured to have the same composition as the test drug, but without the active ingredient in 100 mL of this drug; however, to exhibit a similar taste to the test drug, sweetener (sucrose) has been added compared to the test drug.

[0085] Participants deemed suitable for this clinical trial were randomly assigned in a 1:1:1 ratio to a placebo group, a high-dose group, and a low-dose group during the administration period of the main study (weeks 0-12). Patients assigned to the high-dose or low-dose group received oral AST-001 syrup for 12 weeks according to the administration methods and weight-based dosages described in Table 4. In patients receiving the high-dose dose, the dose equivalent to the low-dose dose was administered for the first two weeks, after which it was increased to the high-dose dose to confirm safety.

[0086] [Table 4]

[0087] As described above, the control group, which received a placebo for 12 weeks, was further administered high-dose AST-001 syrup as shown in Table 4 for an extended study period of 12 weeks (low doses were administered for the first two weeks to confirm safety, followed by high doses), and was classified as the high-dose short-term administration group. In the main study, patients who received high-dose AST-001 injections were classified as the high-dose long-term administration group by receiving continuous injections of high-dose AST-001. In the main study, patients who received low-dose AST-001 injections were classified as the low-dose long-term administration group by receiving continuous injections of low-dose AST-001 syrup. After the 12-week extended study period, patients' efficacy and adverse events were followed up and monitored for 12 weeks (i.e., follow-up period).

[0088] The baseline characteristics of patients (within the FAS population) who participated in the clinical trial are shown in Table 5.

[0089] [Table 5] JPEG2026523093000008.jpg65149

[0090] a: The analysis was performed using Fisher's exact test. Effectiveness In the Phase 2 clinical trial of AST-001 syrup, the primary efficacy endpoint was the change in K-VABS-II ABC score from baseline at 12 weeks post-administration. K-VABS-II is a valid and reproducible assessment tool for evaluating the level of functional adaptation in autism spectrum disorder, and consists of four main domains: communication, life skills, social skills, and motor skills, and a selectively administered domain of maladaptive behavior indicators. Each item is on a 3-point Likert scale (0 points = none, 1 point = sometimes or partially, 2 points = frequently). The primary endpoint, the K-VABS-II adaptive behavior composite (K-VABS-II ABC) score, is a calculated score (standard score) for the main domains, and a higher score indicates a higher level of adaptive behavior. The CGI-S is the Ohio State University (OSU) Autism CGI-S Scale, which assesses overall severity according to a 7-point Likert scale (1 point (normal, not sick at all) to 7 points (among the most severely ill patients) with lower scores indicating lower severity.

[0091] Figure 10 shows the change in K-VABS-II ABC scores for the three groups at weeks 12, 24, and 36 relative to the change in scores at the start of the clinical trial. Figure 11 shows the difference in efficacy between the treatment groups compared to the control group (placebo) for parental distress scores measured by K-VABS-II ABC, main domain, and K-PSI-4-SF at 12 weeks after administration of AST-001 syrup. Figure 12 shows the change in K-VABS-II 2DC scores for the three groups at weeks 12, 24, and 36 relative to the change in scores at the start of the clinical trial.

[0092] Furthermore, Figure 13 shows the score changes for the three groups at weeks 2, 4, 8, 12, 14, 16, 24, and 36, relative to the score change at the start of the Phase 2 clinical trial.

[0093] All analysis results were obtained from the full analysis set (FAS) group, which included all patients who had given written consent to participate in the clinical trial and had received at least one administration of the investigational medicinal product, and for whom efficacy assessment variable data had been collected at least once after the baseline blood sample was taken.

[0094] <Analysis of efficacy at 12 weeks after administration of <AST-001> syrup> The change in the score of K-VABS-II ABC (LS mean ± SE) relative to baseline at 12 weeks after administration of <AST-001> syrup was 1.66 ± 0.48 points in the control group (placebo) and 3.08 ± 0.49 points in the high-dose group. The change in score in the high-dose group was significantly increased compared with the change in score in the control group (see Figure 11), and the difference in the change in score was 1.43 ± 0.69 points [90% confidence interval (CI) 0.28, 2.58], and it was found that this was at a statistically significant level (p = 0.042) (see Figure 11). Therefore, it was confirmed that the administration of <AST-001> syrup improved the level of functional adaptation up to a statistically significant level.

[0095] Administration of <AST-001> syrup improved all of the scores of K-VABS-II ABC, K-VABS-II communication, K-VABS-II daily living skills, and K-VABS-II sociality, as well as the scores of K-VABS-II motor skills and the number of parental distress by K-PSI-4-SF (see Figure 11). In particular, the scores of the K-VABS-II communication and K-VABS-II motor skills domains were significantly improved in the high-dose <AST-001> syrup administration group compared with the control group (p-value 0.007, p-value 0.049, see Figure 11). Furthermore, the number of parental distress by K-PSI-4-SF was significantly improved in the high-dose <AST-001> syrup administration group compared with the control group (p-value 0.027, see Figure 11).

[0096] Furthermore, when the change in K-VABS-II 2DC score was analyzed at 12 weeks after the start of the clinical trial, the change was larger in the low-dose AST-001 syrup administration group and the high-dose AST-001 syrup administration group compared to the control group (see Figure 12), and the change in the high-dose AST-001 syrup administration group was statistically significant compared to the control group (p-value 0.026).

[0097] Furthermore, baseline mean CGI-S scores and mean CGI-S scores at 12 weeks of AST-001 syrup administration, reflecting age, were found to be significantly improved in both the high-dose and low-dose groups compared to the control group (see Figure 13). The difference in score changes between the two groups was statistically significant (p-value 0.046 for high-dose group versus control group, and p-value 0.017 for low-dose group versus control group).

[0098] Furthermore, when small-group efficacy analysis was performed with patients aged 7 or 6 years participating in the clinical trial, the results of the K-VABS-II ABC analysis are shown in Table 6.

[0099] [Table 6]

[0100] As confirmed in Table 6 above, in patients aged 7 years or younger and those under 7 years of age who received high-dose and low-dose AST-001 syrup injections, the change in K-VABS-II ABC scores at 12 weeks was significantly improved compared to the baseline compared to the control group. As a result, it was found that the improvement effect on autism spectrum disorder was high in the group of patients aged 7 years or younger and those under 7 years of age, suggesting that early treatment at the critical period when synaptic pruning is achieved is effective in improving the disease.

[0101] Furthermore, among the FAS population, a patient population (PPS) that completed the clinical trial without any major violations of the clinical trial protocol was selected, and the PPS population was subjected to an analysis of the change in the score of K-VABS-II ABC at the 12-week time point, which is the primary efficacy evaluation variable. In the PPS population, the degree of improvement of the low-dose group compared to the control group was more statistically significant compared to the analysis in the FAS population when compared to the high-dose group and the control group (p-value = 0.024, p-value = 0.075) (see Figure 14).

[0102] <Analysis of efficacy at 24 weeks after administration of <AST-001 syrup>> The extension study period from 12 weeks to 24 weeks was the period during which <AST-001 syrup> was administered to all of the high-dose long-term administration group, low-dose long-term administration group, and high-dose short-term administration group. It was confirmed that the improvement in the change in the scores of K-VABS-II ABC and the main domain, as well as 2DC and CGI-S, was greater at the 12-week time point than at the start of the clinical trial and the 24-week time point in all groups (see Figures 10, 12, and 13). In particular, in the high-dose short-term administration group that received high-dose <AST-001> 12 weeks after placebo administration, it was confirmed that the change in the scores of K-VABS-II ABC and the main domain, as well as 2DC and CGI-S, improved significantly at the 24-week time point compared to the 12-week time point. At the scores of K-VABS-II ABC and CGI-S at the 24-week time point, there was no statistically significant difference among the three groups compared to the start of the clinical trial (p-value = 0.555, p-value = 0.441).

[0103] <Analysis of efficacy at 36 weeks after administration of <AST-001 syrup>> On the other hand, the follow-up study period from 24 weeks to 36 weeks after the start of the clinical trial was the period during which follow-up and monitoring were carried out without administering the drug to any of the high-dose long-term administration group, low-dose long-term administration group, and high-dose short-term administration group. There was no statistically significant difference among the three groups in the scores of K-VABS-II ABC and CGI-S in the high-dose long-term administration group, low-dose long-term administration group, and high-dose short-term administration group (p-value = 0.731, p-value = 0.611).

[0104] However, when the effect of drug discontinuation was tracked and monitored for 12 weeks (i.e., weeks 24 to 36) after the completion of AST-001 syrup administration, an examination of each main domain of K-VABS-II at week 36 revealed a slight decrease in the effect of drug discontinuation in all main domains except for the motor skills main domain. This confirmed that the efficacy results showing improvement up to week 24 after administration were due to the effect of AST-001 syrup.

[0105] Furthermore, when the changes in K-VABS-II ABC scores and CSI-S scores were analyzed at 36 weeks after the start of the clinical trial, the numerical values ​​for the changes in K-VABS-II ABC scores and CSI-S scores were highest in the high-dose long-term AST-001 syrup administration group, followed by the low-dose long-term AST-001 syrup administration group, and then the high-dose long-term short-term AST-001 syrup administration group, confirming that the degree of improvement was highest in this order (see Figures 10 and 13).

[0106] As a result, it was confirmed that oral administration of AST-001 syrup at low or high doses to pediatric patients with autism spectrum disorder (AST) improved the core symptoms of autism spectrum disorder.

[0107] safety Table 7 shows the treatment-induced adverse events (TEAEs) that occurred in 5% or more of patients participating in the clinical trial.

[0108] [Table 7]

[0109] During the 36-week clinical trial period, the most frequent adverse events were cough, nasopharyngitis, fever, and diarrhea, in that order. Most adverse events were mild, and the differences in adverse events between the high-dose, low-dose, and control groups were not statistically significant (p=0.115). Five patients (3.3%) experienced serious adverse events unrelated to AST-001 syrup. Drug-related adverse reactions (ADRs) associated with AST-001 syrup were reported in 12 patients (24.0%) in the control group, 6 patients (11.8%) in the low-dose group, and 7 patients (14.0%) in the high-dose group. No statistically significant differences were observed among these groups (p=0.209).

[0110] Based on the above findings, AST-001 syrup administration was found to be superior to the control group in improving symptoms of autism spectrum disorder, such as communication and motor impairments, while also demonstrating superior safety and drug tolerability. Furthermore, the high-dose short-term treatment group, which received a high dose of AST-001 syrup after 12 weeks of placebo administration, showed similar developmental levels to the low-dose long-term treatment group and the high-dose long-term treatment group. In addition, compared to the control group, the AST-001 syrup group showed improved parental stress due to the improvement of the parental distress subdomain mediated by K-PSI-4-SF. As a result, it was confirmed that AST-001 syrup administration can improve core symptoms of autism spectrum disorder and also improve the stress experienced by parents caring for patients with autism spectrum disorder.

[0111] Example 4.5 Clinical trial with 2 weeks of continuous administration Sixty-one patients willing to participate in a continuous administration clinical trial were selected from 75 responders who demonstrated a therapeutic response to AST-001 syrup and completed the Phase 2 clinical trial in Example 3. Each responder received the drug for 52 weeks, and an overview of the clinical trial is shown in Figure 15.

[0112] Respondents are patients in a Phase 2 clinical trial whose K-VABS-II ABC score increased by 4 points or more from baseline at 24 weeks post-administration (end of treatment, EOT), or whose overall improvement level (CGI-Improvement, hereinafter referred to as CGI-I) at 24 weeks post-administration (EOT) was 1 point (very improved) or 2 points (quite improved). CGI-I is the OSU Autism CGI-I Scale, which consists of seven Likert points (1 point (very improved) to 7 points (very worsened)). This represents the overall improvement from baseline in the Phase 2 clinical trial, with a lower score indicating a greater degree of improvement. Selected responders were assigned to one of the treatment groups listed in Table 8, in which case the high-dose and low-dose doses of AST-001 syrup were the doses listed in Table 4.

[0113] [Table 8]

[0114] The baseline status of patients at the start of the 52-week continuous clinical trial is shown in Table 9 below. There were no statistically significant differences between the low-dose and high-dose groups in terms of age, sex, prevalence of comorbid mental disorders, or baseline CGI-S.

[0115] [Table 9]

[0116] Effectiveness Table 10 shows the mean CGI-S scores and the change in CGI-S scores from baseline, measured at the start of the 52-week clinical trial (i.e., baseline), and at weeks 8, 16, 24, 32, 40, and 52.

[0117] [Table 10]

[0118] Furthermore, Figures 16 and 17 show the trends in CGI-S scores and the changes in CGI-S scores for each group of patients participating in the 52-week continuous administration clinical trial, from the start of the Phase 2 clinical trial to the completion of the 52-week continuous administration clinical trial, respectively.

[0119] Both the low-dose and high-dose groups showed a tendency for CGI-S scores to improve during the 52-week continuous administration clinical trial period, with the improvement being greater in the high-dose group compared to the low-dose group. Because the CGI-S score (severity) was higher in the low-dose group at baseline in the continuous administration trial, the low-dose group showed a somewhat larger change than the high-dose group up to the midpoint; however, at the completion of continuous administration (week 52), the high-dose group showed a greater improvement than the low-dose group. Furthermore, the high-dose group showed a high improvement up to the end of 24 weeks of administration (EOT) in the Phase 2 clinical trial. Subsequently, the effect deteriorated temporarily up to the baseline point of the continuous administration trial (the point of discontinuation), but was maintained again with a decrease in severity upon readmission of AST-001 syrup, showing further improvement at week 52.

[0120] Table 11 below shows the mean CGI-I scores and CGI-I response rates (percentage of respondents with a CGI-I score of 1 or 2) measured at the start of the 52-week clinical trial (i.e., baseline), and at weeks 8, 16, 24, 32, 40, and 52.

[0121] [Table 11]

[0122] At baseline in the 52-week continuous administration study, CGI-I scores were lower in the low-dose group compared to the high-dose group. However, at 52 weeks, the high-dose group showed lower CGI-I scores than the low-dose group, indicating a greater degree of improvement during the continuous administration study in the high-dose group compared to the low-dose group. Furthermore, both the low-dose and high-dose groups showed scores between 2 and 3 points, consistently demonstrating improvement in CGI-I assessment throughout the continuous administration study, thus demonstrating the beneficial effect of long-term administration.

[0123] Furthermore, of the 48 subjects whose CGI-I response was evaluated at 24 weeks in the Phase 2 clinical trial, 43 maintained their CGI-I response at baseline in the continuous administration study. Approximately 90% of subjects maintained the improvement in CGI-I in the Phase 2 clinical trial, and approximately 94% of subjects maintained their CGI-I response by the end of the 52-week continuous administration clinical trial.

[0124] Furthermore, when the age of patients participating in the clinical trial was classified into those aged 8 years or older and those aged 7 years or younger, and the efficacy of AST-001 syrup administration was analyzed, it was found that the degree of improvement in CGI-S compared to baseline in the Phase 2 clinical trial was higher in the group aged 7 years or older compared to the group aged 8 years or older (see Table 12).

[0125] [Table 12] Furthermore, the degree of improvement in CGI-1 at 52 weeks during continuous administration was found to be higher in the group aged 7 years or younger compared to the group aged 8 years or older (see Table 13).

[0126] [Table 13]

[0127] In other words, in the Phase 2 clinical trial, the change in CGI-S score relative to baseline and the mean CGI-I score showed that the improvement in autism spectrum disorder was greater in the patient group aged 7 years and under compared to the patient group aged 8 years and older, suggesting that early treatment at the critical period when synaptic pruning is achieved is effective in improving the disease.

[0128] safety During the 52-week continuous administration clinical trial, no serious adverse events or deaths were reported that were assessed as being related to AST-001. Of the 41 TEAEs (Triple Advanced Adverse Events) reported during the 52-week continuous administration clinical trial conducted amid the COVID-19 pandemic, COVID-19 infection was reported as the most frequent adverse event (5 events in the low-dose group and 6 events in the high-dose group) (see Table 14 below).

[0129] [Table 14]

[0130] Furthermore, a total of two adverse drug reactions (ADRs) were Grade 1 (mild) adverse events, and these were confirmed to have "recovered" after the adverse events. As a result, it was found that safe administration was possible to pediatric patients with autism spectrum disorder without discontinuing treatment for up to 52 weeks of continuous administration.

[0131] In summary, AST-001 syrup can be safely administered long-term to pediatric patients with autism spectrum disorder, and its efficacy tended to improve with longer continuous administration periods. Furthermore, it was confirmed that not only was the treatment response shown in the Phase 2 clinical trial sustained overall, but that further improvements could be obtained with long-term administration.

[0132] Example 5. Dosage / Administrative Modeling Analysis in Phase 3 Clinical Trials Considering that one sachet of AST-001 syrup used in the clinical trial is a 2g / 20mL formulation, a modeling analysis was performed to evaluate whether the effects confirmed in the Phase 2 clinical trial would be achieved even if the single dose for each weight range was set to an even number of sachets, in order to improve ease of administration to children.

[0133] For modeling analysis, population pharmacokinetic / pharmacodynamic models were constructed using clinical trial data obtained from the clinical trial in healthy adult males in Example 2.2 and the Phase 2 clinical trial in Example 3. The Monolix program (version 2021R1) was used for population pharmacokinetic / pharmacodynamic analysis of AST-001. Parameter estimation was performed using a stochastic approximate expectation maximization algorithm, following the clinical trial protocols of Examples 2.2 and 3, with clinical trial data and KVABS-II-ABC score data. In the model constructed in Example 2.3, a model excluding endogenous L-serine production was used as the population pharmacokinetic model. Turnover models, effect compartment models, and direct models were investigated for pharmacodynamic models, and linear and Emax models were investigated for drug effects. Constant, linear, and exponential models were investigated for the time-dependent patterns of K-VABS-II-ABC score changes, including the placebo group.

[0134] Using the final pharmacokinetic / pharmacodynamic model, we performed simulation analyses to predict the patterns of K-VABS-II-ABC scores when AST-001 was administered for 12 weeks for each weight group, according to several scenarios.

[0135] Simulx (version 2021R1) was used for the simulation analysis, and data from 1,000 to 1,200 children aged 2 to 12 years was generated and analyzed using the "httk" package of the R software. Dosages 1, 3, and 4 based on body weight in the simulation scenarios were analyzed using data from 1,000 virtual pediatric patients, and dose 2 based on body weight was analyzed using data from 1,200 virtual pediatric patients. The ratio of subjects whose KVABS-II-ABC score change increased by 2 points or more at 12 weeks (= target achievement) was explored, and the doses in the scenarios that were expected to achieve a similar level of target achievement as the dosage used in each weight range in the Phase 2 clinical trial were found to be easy to administer and produced the effects confirmed in the Phase 2 clinical trial.

[0136] [Population pharmacokinetic / pharmacodynamic analysis results] The pharmacodynamic pattern of AST-001 syrup was adequately explained by a model in which the drug effect is linearly represented according to the site-of-effect concentration, and the change in K-VABS-II-ABC score was included in the linear progression model regardless of drug administration. The final model was analyzed to adequately predict the pharmacodynamic pattern after AST-001 syrup administration using GOF and VPC.

[0137] [Simulation analysis results] When comparing the results obtained by administering AST-001 syrup for 12 weeks according to the BID dosage in several adopted scenarios with the simulation results of the dosage for each weight range in which the drug was administered in the Phase 2 clinical trial, the results from the four weight-based dosage scenarios were the most similar in reaching the target efficacy. Figure 18 shows the analysis results obtained by predicting the pattern of K-VABS-II-ABC scores over 12 weeks in this case.

[0138] Specifically, the median change in K-VABS-II-ABC score from week 0 to week 12 was predicted to be 1.67–3.74 in the AST-001 syrup treatment group and 0.92–1.15 in the placebo group (see Figure 18). Furthermore, when 2g BID was administered to children in the 10–13kg weight range, the proportion of pediatric patients whose K-VABS-II-ABC score increased by 2 points or more (target achievement rate) was 40.5%, which was 2.1 times higher than in the placebo group. In addition, in other weight ranges, the proportion of target achievement rates was confirmed to be 1.8–2.7 times higher in the AST-001 syrup treatment group compared to the placebo group (see Figure 18).

[0139] Therefore, considering the ease of administration in children and the efficacy of AST-001 syrup, it was analyzed that AST-001 syrup, when administered at the dosages listed in Table 15 for each weight range, showed clinically significant efficacy compared to placebo.

[0140] [Table 15]

Claims

1. A pharmaceutical composition for treating individuals having a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders, comprising L-serine or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the autism spectrum disorder is childhood autism.

3. The pharmaceutical composition according to claim 1 or 2, wherein the L-serine or a pharmaceutically acceptable salt thereof is administered to the individual twice daily.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is a formulation for oral administration.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is a syrup formulation.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the individual is 18 years of age or younger.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual is 13 years old or younger, 11 years old or younger, 7 years old or younger, under 7 years old, 2 to 7 years old, or 2 to 6 years old.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the weight of the individual is 10 to 100 kg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the weight of the individual is 10 to 60 kg.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 1 g to 60 g.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 2 g to 30 g or 2 g to 28 g.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 2 g to 15 g or 2 g to 14 g.

13. The pharmaceutical composition according to any one of claims 1 to 10, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 4 g to 30 g or 4 g to 28 g.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 100 mg / kg to 600 mg / kg.

15. The pharmaceutical composition according to claim 14, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 140 mg / kg to 580 mg / kg or 140 mg / kg to 572 mg / kg.

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg.

17. The pharmaceutical composition according to any one of claims 1 to 14, wherein the single dose of L-serine or a pharmaceutically acceptable salt thereof is 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg.

18. A pharmaceutical composition according to any one of claims 1 to 17, further comprising one or more of a sweetener, a thickener, a pH adjuster, a preservative, and a solvent.

19. A method for treating a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders, comprising the step of administering L-serine or a pharmaceutically acceptable salt thereof to an individual having said disorder.

20. A method for treating the disorder according to claim 19, wherein the autism spectrum disorder is childhood autism.

21. A method for treating the disease according to claim 19 or 20, wherein the L-serine or a pharmaceutically acceptable salt thereof is administered to the individual twice daily.

22. A method for treating the disease according to any one of claims 19 to 21, wherein the L-serine or a pharmaceutically acceptable salt thereof is orally administered to the individual.

23. A method for treating the disease according to any one of claims 19 to 22, wherein the L-serine or a pharmaceutically acceptable salt thereof is administered to the individual as a syrup formulation.

24. A method for treating the disease described in any one of claims 19 to 23, wherein the individual is 18 years of age or younger.

25. A method for treating the disease described in any one of claims 19 to 24, wherein the individual is 13 years of age or younger, 11 years of age or younger, 7 years of age or younger, under 7 years of age, 2 to 7 years of age, or 2 to 6 years of age.

26. A method for treating the disease described in any one of claims 19 to 25, wherein the weight of the individual is between 10 kg and 100 kg.

27. A method for treating the disease according to any one of claims 19 to 26, wherein the weight of the individual is between 10 kg and 60 kg.

28. A method for treating the disease according to any one of claims 19 to 27, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 1 g to 60 g.

29. A method for treating the disease according to any one of claims 19 to 28, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 2 g to 30 g or 2 g to 28 g.

30. A method for treating the disease according to any one of claims 19 to 28, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 2 g to 15 g or 2 g to 14 g.

31. A method for treating the disease according to any one of claims 19 to 28, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 4 g to 30 g or 4 g to 28 g.

32. A method for treating the disease according to any one of claims 19 to 31, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 100 mg / kg to 600 mg / kg.

33. A method for treating the disease according to claim 32, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 140 mg / kg to 580 mg / kg or 140 mg / kg to 572 mg / kg.

34. A method for treating the disease according to any one of claims 19 to 31, wherein the total daily dose of L-serine or a pharmaceutically acceptable salt thereof is 200 mg / kg to 400 mg / kg, 280 mg / kg to 580 mg / kg, or 280 mg / kg to 572 mg / kg.

35. A method for treating the disease according to any one of claims 19 to 31, wherein the single dose of L-serine or a pharmaceutically acceptable salt thereof is 70 mg / kg to 280 mg / kg, 140 mg / kg to 290 mg / kg, or 140 mg / kg to 286 mg / kg.

36. Use of the pharmaceutical composition according to any one of claims 1 to 18 for manufacturing a pharmaceutical for improving, preventing or treating a disorder selected from communication disorders, motor impairments, cognitive impairments, mental disorders, sensory impairments, autism spectrum disorders, and pervasive developmental disorders.

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